50 results on '"Venn NC"'
Search Results
2. Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.
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Venn, NC, Huang, L, Hovorková, L, Muskovic, W, Wong, M, Law, T, Heatley, SL, Khaw, SL, Revesz, T, Dalla Pozza, L, Shaw, PJ, Fraser, C, Moore, AS, Cross, S, Bendak, K, Norris, MD, Henderson, MJ, White, DL, Cowley, MJ, Trahair, TN, Zuna, J, Sutton, R, Venn, NC, Huang, L, Hovorková, L, Muskovic, W, Wong, M, Law, T, Heatley, SL, Khaw, SL, Revesz, T, Dalla Pozza, L, Shaw, PJ, Fraser, C, Moore, AS, Cross, S, Bendak, K, Norris, MD, Henderson, MJ, White, DL, Cowley, MJ, Trahair, TN, Zuna, J, and Sutton, R
- Abstract
BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.
- Published
- 2022
3. Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma
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Subhash, VV, Huang, L, Kamili, A, Wong, M, Chen, D, Venn, NC, Atkinson, C, Mayoh, C, Venkat, P, Tyrrell, V, Marshall, GM, Cowley, MJ, Ekert, PG, Norris, MD, Haber, M, Henderson, MJ, Sutton, R, Fletcher, JI, Trahair, TN, Subhash, VV, Huang, L, Kamili, A, Wong, M, Chen, D, Venn, NC, Atkinson, C, Mayoh, C, Venkat, P, Tyrrell, V, Marshall, GM, Cowley, MJ, Ekert, PG, Norris, MD, Haber, M, Henderson, MJ, Sutton, R, Fletcher, JI, and Trahair, TN
- Abstract
Background: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. Methods: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each). Results: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10−4 (0.01%)–10–5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. Conclusions: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.
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- 2021
4. Two novel cases of NUTM1-rearranged B-cell acute lymphoblastic leukaemia presenting with high-risk features
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McClure, BJ, Pal, M, Heatley, SL, Rehn, J, Schutz, C, Breen, J, Venn, NC, Sutton, R, Khaw, SL, Yeung, DT, White, DL, McClure, BJ, Pal, M, Heatley, SL, Rehn, J, Schutz, C, Breen, J, Venn, NC, Sutton, R, Khaw, SL, Yeung, DT, and White, DL
- Published
- 2021
5. Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab.
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Sutton, R, Pozza, LD, Khaw, SL, Fraser, C, Revesz, T, Chamberlain, J, Mitchell, R, Trahair, TN, Bateman, CM, Venn, NC, Law, T, Ong, E, Heatley, SL, McClure, BJ, Meyer, C, Marschalek, R, Henderson, MJ, Cross, S, White, DL, Kotecha, RS, Sutton, R, Pozza, LD, Khaw, SL, Fraser, C, Revesz, T, Chamberlain, J, Mitchell, R, Trahair, TN, Bateman, CM, Venn, NC, Law, T, Ong, E, Heatley, SL, McClure, BJ, Meyer, C, Marschalek, R, Henderson, MJ, Cross, S, White, DL, and Kotecha, RS
- Abstract
We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B-cell acute lymphoblastic leukaemia (B-ALL) and high-risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2-year progression-free survival (PFS) of 39% and 2-year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19-directed chimeric antigen receptor T-cell therapy despite prior blinatumomab exposure. Inferior 2-year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A-rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B-ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.
- Published
- 2021
6. The application of RNA sequencing for the diagnosis and genomic classification of pediatric acute lymphoblastic leukemia
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Brown, LM, Lonsdale, A, Zhu, A, Davidson, NM, Schmidt, B, Hawkins, A, Wallach, E, Martin, M, Mechinaud, FM, Khaw, SL, Bartolo, RC, Ludlow, LEA, Challis, J, Brooks, I, Petrovic, V, Venn, NC, Sutton, R, Majewski, IJ, Oshlack, A, Ekert, PG, Brown, LM, Lonsdale, A, Zhu, A, Davidson, NM, Schmidt, B, Hawkins, A, Wallach, E, Martin, M, Mechinaud, FM, Khaw, SL, Bartolo, RC, Ludlow, LEA, Challis, J, Brooks, I, Petrovic, V, Venn, NC, Sutton, R, Majewski, IJ, Oshlack, A, and Ekert, PG
- Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of risk-adapted therapy has been instrumental in the dramatic improvements in clinical outcomes. A key to risk-adapted therapies includes the identification of genomic features of individual tumors, including chromosome number (for hyper- and hypodiploidy) and gene fusions, notably ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 in B-cell ALL (B-ALL). RNA-sequencing (RNA-seq) of large ALL cohorts has expanded the number of recurrent gene fusions recognized as drivers in ALL, and identification of these new entities will contribute to refining ALL risk stratification. We used RNA-seq on 126 ALL patients from our clinical service to test the utility of including RNA-seq in standard-of-care diagnostic pipelines to detect gene rearrangements and IKZF1 deletions. RNA-seq identified 86% of rearrangements detected by standard-of-care diagnostics. KMT2A (MLL) rearrangements, although usually identified, were the most commonly missed by RNA-seq as a result of low expression. RNA-seq identified rearrangements that were not detected by standard-of-care testing in 9 patients. These were found in patients who were not classifiable using standard molecular assessment. We developed an approach to detect the most common IKZF1 deletion from RNA-seq data and validated this using an RQ-PCR assay. We applied an expression classifier to identify Philadelphia chromosome-like B-ALL patients. T-ALL proved a rich source of novel gene fusions, which have clinical implications or provide insights into disease biology. Our experience shows that RNA-seq can be implemented within an individual clinical service to enhance the current molecular diagnostic risk classification of ALL.
- Published
- 2020
7. Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions
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Meyer, C, Lopes, BA, Caye-Eude, A, Cavé, H, Arfeuille, C, Cuccuini, W, Sutton, R, Venn, NC, Oh, SH, Tsaur, G, Escherich, G, Feuchtinger, T, Kosasih, HJ, Khaw, SL, Ekert, PG, Pombo-de-Oliveira, MS, Bidet, A, Djahanschiri, B, Ebersberger, I, Zaliova, M, Zuna, J, Zermanova, Z, Juvonen, V, Grümayer, RP, Fazio, G, Cazzaniga, G, Larghero, P, Emerenciano, M, Marschalek, R, Meyer, C, Lopes, BA, Caye-Eude, A, Cavé, H, Arfeuille, C, Cuccuini, W, Sutton, R, Venn, NC, Oh, SH, Tsaur, G, Escherich, G, Feuchtinger, T, Kosasih, HJ, Khaw, SL, Ekert, PG, Pombo-de-Oliveira, MS, Bidet, A, Djahanschiri, B, Ebersberger, I, Zaliova, M, Zuna, J, Zermanova, Z, Juvonen, V, Grümayer, RP, Fazio, G, Cazzaniga, G, Larghero, P, Emerenciano, M, and Marschalek, R
- Published
- 2019
8. The MLL recombinome of acute leukemias in 2017
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Meyer, C, Burmeister, T, Groger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, NC, Emerenciano, M, Pombo-de-Oliveira, MS, Blunck, CB, Lopes, BA, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Abascal, LC, van der Velden, Vincent, Delabesse, E, Park, TS, Oh, SH, Silva, MLM, Lund-Aho, T, Juvonen, V, Moore, AS, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, zur Stadt, U, Lentes, J, Gohring, G, Kustanovich, A, Aleinikova, O, Schafer, BW, Kubetzko, S, Madsen, HO, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, JM, Clappier, E, Alonso, CN (Cristina), Zwaan, C.M., Van den Heuvel - Eibrink, Marry, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Moricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, OA, Panzer-Grumayer, R, Sedek, L, Szczepanski, T, Caye, A, Suarez, L, Cave, H, Marschalek, R, Meyer, C, Burmeister, T, Groger, D, Tsaur, G, Fechina, L, Renneville, A, Sutton, R, Venn, NC, Emerenciano, M, Pombo-de-Oliveira, MS, Blunck, CB, Lopes, BA, Zuna, J, Trka, J, Ballerini, P, Lapillonne, H, De Braekeleer, M, Cazzaniga, G, Abascal, LC, van der Velden, Vincent, Delabesse, E, Park, TS, Oh, SH, Silva, MLM, Lund-Aho, T, Juvonen, V, Moore, AS, Heidenreich, O, Vormoor, J, Zerkalenkova, E, Olshanskaya, Y, Bueno, C, Menendez, P, Teigler-Schlegel, A, zur Stadt, U, Lentes, J, Gohring, G, Kustanovich, A, Aleinikova, O, Schafer, BW, Kubetzko, S, Madsen, HO, Gruhn, B, Duarte, X, Gameiro, P, Lippert, E, Bidet, A, Cayuela, JM, Clappier, E, Alonso, CN (Cristina), Zwaan, C.M., Van den Heuvel - Eibrink, Marry, Izraeli, S, Trakhtenbrot, L, Archer, P, Hancock, J, Moricke, A, Alten, J, Schrappe, M, Stanulla, M, Strehl, S, Attarbaschi, A, Dworzak, M, Haas, OA, Panzer-Grumayer, R, Sedek, L, Szczepanski, T, Caye, A, Suarez, L, Cave, H, and Marschalek, R
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- 2018
9. Xenograft-directed personalized therapy for a patient with post-transplant relapse of ALL
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Trahair, TN, Lock, RB, Sutton, R, Sia, KCS, Evans, K, Richmond, J, Law, T, Venn, NC, Irving, JA, Moore, S, Nievergall, E, Dang, P, Heatley, SL, White, DL, Revesz, T, Trahair, TN, Lock, RB, Sutton, R, Sia, KCS, Evans, K, Richmond, J, Law, T, Venn, NC, Irving, JA, Moore, S, Nievergall, E, Dang, P, Heatley, SL, White, DL, and Revesz, T
- Published
- 2016
10. Heterogeneity in mechanisms of emergent resistance in pediatric T-cell acute lymphoblastic leukemia
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Yadav, BD, Samuels, AL, Wells, JE, Sutton, R, Venn, NC, Bendak, K, Anderson, D, Marshall, GM, Cole, CH, Beesley, AH, Kees, UR, Lock, RB, Yadav, BD, Samuels, AL, Wells, JE, Sutton, R, Venn, NC, Bendak, K, Anderson, D, Marshall, GM, Cole, CH, Beesley, AH, Kees, UR, and Lock, RB
- Abstract
Relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem and is thought to be associated with clonal selection during treatment. In this study we used an established pre-clinical model of induction therapy to increase our understanding of the effect of engraftment and chemotherapy on clonal selection and acquisition of drug resistance in vivo. Immune-deficient mice were engrafted with patient diagnostic specimens and exposed to a repeated combination therapy consisting of vincristine, dexamethasone, L-asparaginase and daunorubicin. Any re-emergence of disease following therapy was shown to be associated with resistance to dexamethasone, no resistance was observed to the other three drugs. Immunoglobulin/T-cell receptor gene rearrangements closely matched those in respective diagnosis and relapse patient specimens, highlighting that these clonal markers do not fully reflect the biological changes associated with drug resistance. Gene expression profiling revealed the significant underlying heterogeneity of dexamethasone-resistant xenografts. Alterations were observed in a large number of biological pathways, yet no dominant signature was common to all lines. These findings indicate that the biological changes associated with T-ALL relapse and resistance are stochastic and highly individual, and underline the importance of using sophisticated molecular techniques or single cell analyses in developing personalized approaches to therapy.
- Published
- 2016
11. Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia
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Richmond, J, Carol, H, Evans, K, High, L, Mendomo, A, Robbins, A, Meyer, C, Venn, NC, Marschalek, R, Henderson, M, Sutton, R, Kurmasheva, RT, Kees, UR, Houghton, PJ, Smith, MA, Lock, RB, Richmond, J, Carol, H, Evans, K, High, L, Mendomo, A, Robbins, A, Meyer, C, Venn, NC, Marschalek, R, Henderson, M, Sutton, R, Kurmasheva, RT, Kees, UR, Houghton, PJ, Smith, MA, and Lock, RB
- Abstract
Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated. Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. Conclusions: The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation.
- Published
- 2015
12. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
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Andersson, AK, Ma, J, Wang, J, Chen, X, Gedman, AL, Dang, J, Nakitandwe, J, Holmfeldt, L, Parker, M, Easton, J, Huether, R, Kriwacki, R, Rusch, M, Wu, G, Li, Y, Mulder, H, Raimondi, S, Pounds, S, Kang, G, Shi, L, Becksfort, J, Gupta, P, Payne-Turner, D, Vadodaria, B, Boggs, K, Yergeau, D, Manne, J, Song, G, Edmonson, M, Nagahawatte, P, Wei, L, Cheng, C, Pei, D, Sutton, R, Venn, NC, Chetcuti, A, Rush, A, Catchpoole, D, Heldrup, J, Fioretos, T, Lu, C, Ding, L, Pui, C-H, Shurtleff, S, Mullighan, CG, Mardis, ER, Wilson, RK, Gruber, TA, Zhang, J, Downing, JR, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, Andersson, AK, Ma, J, Wang, J, Chen, X, Gedman, AL, Dang, J, Nakitandwe, J, Holmfeldt, L, Parker, M, Easton, J, Huether, R, Kriwacki, R, Rusch, M, Wu, G, Li, Y, Mulder, H, Raimondi, S, Pounds, S, Kang, G, Shi, L, Becksfort, J, Gupta, P, Payne-Turner, D, Vadodaria, B, Boggs, K, Yergeau, D, Manne, J, Song, G, Edmonson, M, Nagahawatte, P, Wei, L, Cheng, C, Pei, D, Sutton, R, Venn, NC, Chetcuti, A, Rush, A, Catchpoole, D, Heldrup, J, Fioretos, T, Lu, C, Ding, L, Pui, C-H, Shurtleff, S, Mullighan, CG, Mardis, ER, Wilson, RK, Gruber, TA, Zhang, J, Downing, JR, and St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
- Abstract
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.
- Published
- 2015
13. High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation
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Marshall, GM, Dalla Pozza, L, Sutton, R, Ng, A, De Groot-Kruseman, HA, Van Der Velden, VH, Venn, NC, Van Den Berg, H, De Bont, ESJM, Maarten Egeler, R, Hoogerbrugge, PM, Kaspers, GJL, Bierings, MB, Van Der Schoot, E, Van Dongen, J, Law, T, Cross, S, Mueller, H, De Haas, V, Haber, M, Révész, T, Alvaro, F, Suppiah, R, Norris, MD, Pieters, R, Marshall, GM, Dalla Pozza, L, Sutton, R, Ng, A, De Groot-Kruseman, HA, Van Der Velden, VH, Venn, NC, Van Den Berg, H, De Bont, ESJM, Maarten Egeler, R, Hoogerbrugge, PM, Kaspers, GJL, Bierings, MB, Van Der Schoot, E, Van Dongen, J, Law, T, Cross, S, Mueller, H, De Haas, V, Haber, M, Révész, T, Alvaro, F, Suppiah, R, Norris, MD, and Pieters, R
- Abstract
Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt- Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement. © 2013 Macmillan Publishers Limited.
- Published
- 2013
14. Improving the Identification of High Risk Precursor B Acute Lymphoblastic Leukemia Patients with Earlier Quantification of Minimal Residual Disease
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Karsa, M, Dalla Pozza, L, Venn, NC, Law, T, Shi, R, Giles, JE, Bahar, AY, Cross, S, Catchpoole, D, Haber, M, Marshall, GM, Norris, MD, Sutton, R, Karsa, M, Dalla Pozza, L, Venn, NC, Law, T, Shi, R, Giles, JE, Bahar, AY, Cross, S, Catchpoole, D, Haber, M, Marshall, GM, Norris, MD, and Sutton, R
- Abstract
The stratification of patients with acute lymphoblastic leukemia (ALL) into treatment risk groups based on quantification of minimal residual disease (MRD) after induction therapy is now well accepted but the relapse rate of about 20% in intermediate risk patients remains a challenge. The purpose of this study was to further improve stratification by MRD measurement at an earlier stage. MRD was measured in stored day 15 bone marrow samples for pediatric patients enrolled on ANZCHOG ALL8 using Real-time Quantitative PCR to detect immunoglobulin and T-cell receptor gene rearrangements with the same assays used at day 33 and day 79 in the original MRD stratification. MRD levels in bone marrow at day 15 and 33 were highly predictive of outcome in 223 precursor B-ALL patients (log rank Mantel-Cox tests both P<0.001) and identified patients with poor, intermediate and very good outcomes. The combined use of MRD at day 15 (≥1×10-2) and day 33 (≥5×1-5) identified a subgroup of medium risk precursor B-ALL patients as poor MRD responders with 5 year relapse-free survival of 55% compared to 84% for other medium risk patients (log rank Mantel-Cox test, P = 0.0005). Risk stratification of precursor B-ALL but not T-ALL could be improved by using MRD measurement at day 15 and day 33 instead of day 33 and day 79 in similar BFM-based protocols for children with this disease. © 2013 Karsa et al.
- Published
- 2013
15. The MLL recombinome of acute leukemias in 2013
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Meyer, Claus, Hofmann, J, Burmeister, Thomas, Gröger, D, Park, TS, Emerenciano, M, Pombo de Oliveira, M, Renneville, A, Macintyre, E, Cavé, H, Clappier, E, Mass-Malo, K, Zuna, J, Trka, J, De Braekeleer, E, De Braekeleer, M, Oh, SH, Tsaur, G, Fechina, L, van der Velden, VH, van Dongen, JJ, Delabesse, E, Binato, R, Silva, ML, Kustanovich, A, Aleinikova, O, Harris, MH, Lund-Aho, T, Juvonen, V, Heidenreich, Olaf Torben, Vormoor, J, Choi, WW, Jarosova, M, Kolenova, A, Bueno, C, Menendez, P, Wehner, S, Eckert, C, Talmant, P, Tondeur, S, Lippert, E, Launay, E, Henry, C, Ballerini, P, Lapillone, H, Callanan, MB, Cayuela, JM, Herbaux, C, Cazzaniga, G, Kakadiya, PM, Bohlander, Stefan Klaus, Ahlmann, M, Choi, JR, Gameiro, P, Lee, DS, Krauter, J, Cornillet-Lefebvre, P, Te Kronnie, G, Schäfer, BW, Kubetzko, S, Alonso, CN, zur Stadt, U, Sutton, R, Venn, NC, Izraeli, S, Trakhtenbrot, L, Madsen, HO, Archer, P, Hancock, J, Cerveira, N, Teixeira, MR, Lo Nigro, L, Möricke, A, Stanulla, M, Schrappe, M, Sedék, L, Szczepański, T, Zwaan, CM, Coenen, EA, van den Heuvel-Eibrink, MM, Strehl, S, Dworzak, Michael N., Panzer-Grümayer, Renate, Dingermann, Theodor, Klingebiel, Thomas, Marschalek, Rolf, Meyer, Claus, Hofmann, J, Burmeister, Thomas, Gröger, D, Park, TS, Emerenciano, M, Pombo de Oliveira, M, Renneville, A, Macintyre, E, Cavé, H, Clappier, E, Mass-Malo, K, Zuna, J, Trka, J, De Braekeleer, E, De Braekeleer, M, Oh, SH, Tsaur, G, Fechina, L, van der Velden, VH, van Dongen, JJ, Delabesse, E, Binato, R, Silva, ML, Kustanovich, A, Aleinikova, O, Harris, MH, Lund-Aho, T, Juvonen, V, Heidenreich, Olaf Torben, Vormoor, J, Choi, WW, Jarosova, M, Kolenova, A, Bueno, C, Menendez, P, Wehner, S, Eckert, C, Talmant, P, Tondeur, S, Lippert, E, Launay, E, Henry, C, Ballerini, P, Lapillone, H, Callanan, MB, Cayuela, JM, Herbaux, C, Cazzaniga, G, Kakadiya, PM, Bohlander, Stefan Klaus, Ahlmann, M, Choi, JR, Gameiro, P, Lee, DS, Krauter, J, Cornillet-Lefebvre, P, Te Kronnie, G, Schäfer, BW, Kubetzko, S, Alonso, CN, zur Stadt, U, Sutton, R, Venn, NC, Izraeli, S, Trakhtenbrot, L, Madsen, HO, Archer, P, Hancock, J, Cerveira, N, Teixeira, MR, Lo Nigro, L, Möricke, A, Stanulla, M, Schrappe, M, Sedék, L, Szczepański, T, Zwaan, CM, Coenen, EA, van den Heuvel-Eibrink, MM, Strehl, S, Dworzak, Michael N., Panzer-Grümayer, Renate, Dingermann, Theodor, Klingebiel, Thomas, and Marschalek, Rolf
- Abstract
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (~ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
- Published
- 2013
16. Highly sensitive MRD tests for ALL based on the IKZF1 Delta 3-6 microdeletion
- Author
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Venn, NC, Van der velden, VHJ, De bie, M, Waanders, E, Giles, JE, Law, T, Kuiper, RP, de Haas, V, Mullighan, CG, Haber, M, Marshall, GM, Norris, MD, Van dongen, JJM, Sutton, R, Giles, J, Venn, NC, Van der velden, VHJ, De bie, M, Waanders, E, Giles, JE, Law, T, Kuiper, RP, de Haas, V, Mullighan, CG, Haber, M, Marshall, GM, Norris, MD, Van dongen, JJM, Sutton, R, and Giles, J
- Abstract
No abstract available.
- Published
- 2012
17. Highly sensitive MRD tests for ALL based on the IKZF1 Δ3-6 microdeletion.
- Author
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Venn NC, van der Velden VH, de Bie M, Waanders E, Giles JE, Law T, Kuiper RP, de Haas V, Mullighan CG, Haber M, Marshall GM, Md N, van Dongen JJ, Sutton R, Venn, N C, van der Velden, V H J, de Bie, M, Waanders, E, Giles, J E, and Law, T
- Published
- 2012
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18. The recombinome of IKZF1 deletions in B-cell precursor ALL.
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Lopes BA, Meyer C, Bouzada H, Külp M, Maciel ALT, Larghero P, Barbosa TC, Poubel CP, Barbieri C, Venn NC, Pozza LD, Barbaric D, Palmi C, Fazio G, Saitta C, Aguiar TF, Lins MM, Ikoma-Colturato MRV, Schramm M, Chapchap E, Cazzaniga G, Sutton R, Marschalek R, and Emerenciano M
- Subjects
- Humans, Gene Deletion, Prognosis, Ikaros Transcription Factor genetics, Transcription Factors, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2023
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19. The KMT2A recombinome of acute leukemias in 2023.
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Meyer C, Larghero P, Almeida Lopes B, Burmeister T, Gröger D, Sutton R, Venn NC, Cazzaniga G, Corral Abascal L, Tsaur G, Fechina L, Emerenciano M, Pombo-de-Oliveira MS, Lund-Aho T, Lundán T, Montonen M, Juvonen V, Zuna J, Trka J, Ballerini P, Lapillonne H, Van der Velden VHJ, Sonneveld E, Delabesse E, de Matos RRC, Silva MLM, Bomken S, Katsibardi K, Keernik M, Grardel N, Mason J, Price R, Kim J, Eckert C, Lo Nigro L, Bueno C, Menendez P, Zur Stadt U, Gameiro P, Sedék L, Szczepański T, Bidet A, Marcu V, Shichrur K, Izraeli S, Madsen HO, Schäfer BW, Kubetzko S, Kim R, Clappier E, Trautmann H, Brüggemann M, Archer P, Hancock J, Alten J, Möricke A, Stanulla M, Lentes J, Bergmann AK, Strehl S, Köhrer S, Nebral K, Dworzak MN, Haas OA, Arfeuille C, Caye-Eude A, Cavé H, and Marschalek R
- Subjects
- Humans, Infant, Child, Preschool, Child, Adolescent, Adult, Middle Aged, Aged, Gene Fusion, Leukemia, Myeloid, Acute genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival., (© 2023. The Author(s).)
- Published
- 2023
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20. Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.
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Venn NC, Huang L, Hovorková L, Muskovic W, Wong M, Law T, Heatley SL, Khaw SL, Revesz T, Dalla Pozza L, Shaw PJ, Fraser C, Moore AS, Cross S, Bendak K, Norris MD, Henderson MJ, White DL, Cowley MJ, Trahair TN, Zuna J, and Sutton R
- Subjects
- Child, Humans, Immunoglobulins, Neoplasm, Residual genetics, Receptors, Antigen, T-Cell genetics, Fusion Proteins, bcr-abl genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Background: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers., Methods: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines., Results: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001)., Conclusions: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL., (© 2022. The Author(s).)
- Published
- 2022
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21. Two novel cases of NUTM1-rearranged B-cell acute lymphoblastic leukaemia presenting with high-risk features.
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McClure BJ, Pal M, Heatley SL, Rehn J, Schutz C, Breen J, Venn NC, Sutton R, Khaw SL, Yeung DT, and White DL
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- Gene Rearrangement, Humans, Neoplasm Proteins, Nuclear Proteins, Receptors, Cytokine genetics, Transcription Factors, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2022
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22. Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma.
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Subhash VV, Huang L, Kamili A, Wong M, Chen D, Venn NC, Atkinson C, Mayoh C, Venkat P, Tyrrell V, Marshall GM, Cowley MJ, Ekert PG, Norris MD, Haber M, Henderson MJ, Sutton R, Fletcher JI, and Trahair TN
- Subjects
- Adolescent, Bone Neoplasms blood, Bone Neoplasms genetics, Bone Neoplasms pathology, Child, Child, Preschool, Female, Humans, Infant, Male, N-Myc Proto-Oncogene Protein genetics, Neoplasm, Residual genetics, Neuroblastoma blood, Neuroblastoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Protein c-fli-1 genetics, Receptors, Antigen, T-Cell genetics, Sarcoma, Ewing blood, Sarcoma, Ewing genetics, Transcriptional Regulator ERG genetics, Biomarkers, Tumor genetics, Gene Rearrangement, Neoplasm, Residual pathology, Neuroblastoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Sarcoma, Ewing pathology, Whole Genome Sequencing methods
- Abstract
Background: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA., Methods: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each)., Results: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10
-4 (0.01%)-10-5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays., Conclusions: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours., (© 2021. The Author(s).)- Published
- 2022
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23. Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab.
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Sutton R, Pozza LD, Khaw SL, Fraser C, Revesz T, Chamberlain J, Mitchell R, Trahair TN, Bateman CM, Venn NC, Law T, Ong E, Heatley SL, McClure BJ, Meyer C, Marschalek R, Henderson MJ, Cross S, White DL, and Kotecha RS
- Subjects
- Australia, Child, Female, Humans, Male, Neoplasm Recurrence, Local drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Retrospective Studies, Treatment Outcome, Antibodies, Bispecific therapeutic use, Antineoplastic Agents therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B-cell acute lymphoblastic leukaemia (B-ALL) and high-risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2-year progression-free survival (PFS) of 39% and 2-year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19-directed chimeric antigen receptor T-cell therapy despite prior blinatumomab exposure. Inferior 2-year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A-rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B-ALL respond to blinatumomab and factors such as blast genotype may affect prognosis., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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24. CKLF and IL1B transcript levels at diagnosis are predictive of relapse in children with pre-B-cell acute lymphoblastic leukaemia.
- Author
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Fitter S, Bradey AL, Kok CH, Noll JE, Wilczek VJ, Venn NC, Law T, Paisitkriangkrai S, Story C, Saunders L, Dalla Pozza L, Marshall GM, White DL, Sutton R, Zannettino ACW, and Revesz T
- Subjects
- Acute Disease, Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Predictive Value of Tests, Recurrence, Risk Assessment standards, Survival Analysis, Transcriptome genetics, Treatment Failure, Chemokines genetics, Interleukin-1beta genetics, MARVEL Domain-Containing Proteins genetics, Machine Learning statistics & numerical data, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Disease relapse is the greatest cause of treatment failure in paediatric B-cell acute lymphoblastic leukaemia (B-ALL). Current risk stratifications fail to capture all patients at risk of relapse. Herein, we used a machine-learning approach to identify B-ALL blast-secreted factors that are associated with poor survival outcomes. Using this approach, we identified a two-gene expression signature (CKLF and IL1B) that allowed identification of high-risk patients at diagnosis. This two-gene expression signature enhances the predictive value of current at diagnosis or end-of-induction risk stratification suggesting the model can be applied continuously to help guide implementation of risk-adapted therapies., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2021
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25. The application of RNA sequencing for the diagnosis and genomic classification of pediatric acute lymphoblastic leukemia.
- Author
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Brown LM, Lonsdale A, Zhu A, Davidson NM, Schmidt B, Hawkins A, Wallach E, Martin M, Mechinaud FM, Khaw SL, Bartolo RC, Ludlow LEA, Challis J, Brooks I, Petrovic V, Venn NC, Sutton R, Majewski IJ, Oshlack A, and Ekert PG
- Subjects
- Child, Gene Rearrangement, Genomics, Humans, Sequence Analysis, RNA, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of risk-adapted therapy has been instrumental in the dramatic improvements in clinical outcomes. A key to risk-adapted therapies includes the identification of genomic features of individual tumors, including chromosome number (for hyper- and hypodiploidy) and gene fusions, notably ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 in B-cell ALL (B-ALL). RNA-sequencing (RNA-seq) of large ALL cohorts has expanded the number of recurrent gene fusions recognized as drivers in ALL, and identification of these new entities will contribute to refining ALL risk stratification. We used RNA-seq on 126 ALL patients from our clinical service to test the utility of including RNA-seq in standard-of-care diagnostic pipelines to detect gene rearrangements and IKZF1 deletions. RNA-seq identified 86% of rearrangements detected by standard-of-care diagnostics. KMT2A (MLL) rearrangements, although usually identified, were the most commonly missed by RNA-seq as a result of low expression. RNA-seq identified rearrangements that were not detected by standard-of-care testing in 9 patients. These were found in patients who were not classifiable using standard molecular assessment. We developed an approach to detect the most common IKZF1 deletion from RNA-seq data and validated this using an RQ-PCR assay. We applied an expression classifier to identify Philadelphia chromosome-like B-ALL patients. T-ALL proved a rich source of novel gene fusions, which have clinical implications or provide insights into disease biology. Our experience shows that RNA-seq can be implemented within an individual clinical service to enhance the current molecular diagnostic risk classification of ALL., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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26. Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions.
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Meyer C, Lopes BA, Caye-Eude A, Cavé H, Arfeuille C, Cuccuini W, Sutton R, Venn NC, Oh SH, Tsaur G, Escherich G, Feuchtinger T, Kosasih HJ, Khaw SL, Ekert PG, Pombo-de-Oliveira MS, Bidet A, Djahanschiri B, Ebersberger I, Zaliova M, Zuna J, Zermanova Z, Juvonen V, Grümayer RP, Fazio G, Cazzaniga G, Larghero P, Emerenciano M, and Marschalek R
- Subjects
- Cohort Studies, Humans, Leukemia genetics, Translocation, Genetic genetics, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics, Recombinant Fusion Proteins genetics, Ubiquitin Thiolesterase genetics
- Published
- 2019
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27. IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia.
- Author
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Lopes BA, Meyer C, Barbosa TC, Poubel CP, Mansur MB, Duployez N, Bashton M, Harrison CJ, Zur Stadt U, Horstmann M, Pombo-de-Oliveira MS, Palmi C, Cazzaniga G, Venn NC, Sutton R, Alonso CN, Tsaur G, Gupta SK, Bakhshi S, Marschalek R, and Emerenciano M
- Abstract
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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28. A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.
- Author
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Sutton R, Venn NC, Law T, Boer JM, Trahair TN, Ng A, Den Boer ML, Dissanayake A, Giles JE, Dalzell P, Mayoh C, Barbaric D, Revesz T, Alvaro F, Pieters R, Haber M, Norris MD, Schrappe M, Dalla Pozza L, and Marshall GM
- Subjects
- Adolescent, Age Factors, Biomarkers, Tumor, Child, Child, Preschool, Female, Genotype, Humans, Infant, Male, Neoplasm, Residual diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Prognosis, Proportional Hazards Models, Recurrence, Risk Assessment, Risk Factors, Chromosome Deletion, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Sequence Deletion
- Abstract
To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10
-5 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 + for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 + groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL., (© 2017 John Wiley & Sons Ltd.)- Published
- 2018
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29. The MLL recombinome of acute leukemias in 2017.
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Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A, Sutton R, Venn NC, Emerenciano M, Pombo-de-Oliveira MS, Barbieri Blunck C, Almeida Lopes B, Zuna J, Trka J, Ballerini P, Lapillonne H, De Braekeleer M, Cazzaniga G, Corral Abascal L, van der Velden VHJ, Delabesse E, Park TS, Oh SH, Silva MLM, Lund-Aho T, Juvonen V, Moore AS, Heidenreich O, Vormoor J, Zerkalenkova E, Olshanskaya Y, Bueno C, Menendez P, Teigler-Schlegel A, Zur Stadt U, Lentes J, Göhring G, Kustanovich A, Aleinikova O, Schäfer BW, Kubetzko S, Madsen HO, Gruhn B, Duarte X, Gameiro P, Lippert E, Bidet A, Cayuela JM, Clappier E, Alonso CN, Zwaan CM, van den Heuvel-Eibrink MM, Izraeli S, Trakhtenbrot L, Archer P, Hancock J, Möricke A, Alten J, Schrappe M, Stanulla M, Strehl S, Attarbaschi A, Dworzak M, Haas OA, Panzer-Grümayer R, Sedék L, Szczepański T, Caye A, Suarez L, Cavé H, and Marschalek R
- Subjects
- Adult, Child, Chromosome Aberrations, Chromosome Breakage, Female, Gene Rearrangement genetics, Humans, Infant, Male, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic genetics, Histone-Lysine N-Methyltransferase genetics, Leukemia, Myeloid, Acute genetics, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
- Published
- 2018
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30. Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia.
- Author
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Afrin S, Zhang CRC, Meyer C, Stinson CL, Pham T, Bruxner TJC, Venn NC, Trahair TN, Sutton R, Marschalek R, Fink JL, and Moore AS
- Subjects
- Child, Child, Preschool, Cohort Studies, Female, High-Throughput Nucleotide Sequencing methods, Humans, Infant, Infant, Newborn, Leukemia diagnosis, Male, Reagent Kits, Diagnostic, Sensitivity and Specificity, Gene Fusion, Histone-Lysine N-Methyltransferase genetics, Leukemia genetics, Myeloid-Lymphoid Leukemia Protein genetics, Sequence Analysis, DNA methods
- Abstract
Mixed lineage leukemia ( MLL ) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the "gold standard" technique that is used to characterize MLL breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of MLL fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens ( n = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different MLL fusions in the 39 samples. Only two specimens were discordant; AMP-E successfully identified a MLL-MLLT1 fusion where LDI-PCR had failed to determine the breakpoint, whereas a MLL-MLLT3 fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect MLL-AFF1 in MV4-11 cell dilutions of 10
-7 and transcripts down to 0.005 copies/ng. Implications: This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for MLL -rearranged leukemia. Furthermore, this assay rapidly and reliably identifies MLL partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. Mol Cancer Res; 16(2); 279-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2018
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31. Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions.
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Sadras T, Heatley SL, Kok CH, Dang P, Galbraith KM, McClure BJ, Muskovic W, Venn NC, Moore S, Osborn M, Revesz T, Moore AS, Hughes TP, Yeung D, Sutton R, and White DL
- Subjects
- Female, Humans, Interleukin-2 Receptor alpha Subunit genetics, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mucin-4 genetics, Mutation genetics, Oncogene Proteins genetics, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Prognosis, Receptors, G-Protein-Coupled genetics, Tumor Cells, Cultured, Gene Expression Regulation, Leukemic, Gene Rearrangement, Interleukin-2 Receptor alpha Subunit metabolism, Mucin-4 metabolism, Oncogene Proteins metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Receptors, Cytokine genetics, Receptors, G-Protein-Coupled metabolism
- Abstract
CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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32. Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology.
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Hovorkova L, Zaliova M, Venn NC, Bleckmann K, Trkova M, Potuckova E, Vaskova M, Linhartova J, Machova Polakova K, Fronkova E, Muskovic W, Giles JE, Shaw PJ, Cario G, Sutton R, Stary J, Trka J, and Zuna J
- Subjects
- Adolescent, Child, Child, Preschool, Gene Deletion, Hematopoiesis, Humans, Ikaros Transcription Factor genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukocyte Count, Neoplasm, Residual genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Receptors, Antigen, T-Cell genetics, Treatment Outcome, Chromosome Breakage, Fusion Proteins, bcr-abl genetics, Genome, Human, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
We used the genomic breakpoint between BCR and ABL1 genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of IKZF1 deletion, we observed very good correlation for the methods in a majority of patients; however, >20% of children (25% [8/32] with minor and 12.5% [1/8] with major- BCR-ABL1 variants in the consecutive cohorts) had significantly (>1 log) higher levels of BCR-ABL1 fusion than Ig/TCR rearrangements and/or IKZF1 deletion. We performed cell sorting of the diagnostic material and assessed the frequency of BCR-ABL1 -positive cells in various hematopoietic subpopulations; 12% to 83% of non-ALL B lymphocytes, T cells, and/or myeloid cells harbored the BCR-ABL1 fusion in patients with discrepant MRD results. The multilineage involvement of the BCR-ABL1 -positive clone demonstrates that in some patients diagnosed with BCR-ABL1 -positive ALL, a multipotent hematopoietic progenitor is affected by the BCR-ABL1 fusion. These patients have BCR-ABL1 -positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)-like disease manifesting in "lymphoid blast crisis." The biological heterogeneity of BCR-ABL1 -positive ALL may impact the patient outcomes and optimal treatment (early stem cell transplantation vs long-term administration of tyrosine-kinase inhibitors) as well as on MRD testing. Therefore, we recommend further investigations on CML-like BCR-ABL1 -positive ALL., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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33. Heterogeneity in mechanisms of emergent resistance in pediatric T-cell acute lymphoblastic leukemia.
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Yadav BD, Samuels AL, Wells JE, Sutton R, Venn NC, Bendak K, Anderson D, Marshall GM, Cole CH, Beesley AH, Kees UR, and Lock RB
- Subjects
- Animals, Asparaginase therapeutic use, Cell Line, Tumor, Child, Clonal Selection, Antigen-Mediated, Clone Cells, Daunorubicin therapeutic use, Dexamethasone therapeutic use, Drug Resistance, Neoplasm, Humans, Immunocompromised Host, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Receptors, Antigen, T-Cell genetics, Vincristine therapeutic use, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, T-Lymphocytes physiology
- Abstract
Relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem and is thought to be associated with clonal selection during treatment. In this study we used an established pre-clinical model of induction therapy to increase our understanding of the effect of engraftment and chemotherapy on clonal selection and acquisition of drug resistance in vivo. Immune-deficient mice were engrafted with patient diagnostic specimens and exposed to a repeated combination therapy consisting of vincristine, dexamethasone, L-asparaginase and daunorubicin. Any re-emergence of disease following therapy was shown to be associated with resistance to dexamethasone, no resistance was observed to the other three drugs. Immunoglobulin/T-cell receptor gene rearrangements closely matched those in respective diagnosis and relapse patient specimens, highlighting that these clonal markers do not fully reflect the biological changes associated with drug resistance. Gene expression profiling revealed the significant underlying heterogeneity of dexamethasone-resistant xenografts. Alterations were observed in a large number of biological pathways, yet no dominant signature was common to all lines. These findings indicate that the biological changes associated with T-ALL relapse and resistance are stochastic and highly individual, and underline the importance of using sophisticated molecular techniques or single cell analyses in developing personalized approaches to therapy.
- Published
- 2016
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34. Xenograft-directed personalized therapy for a patient with post-transplant relapse of ALL.
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Trahair TN, Lock RB, Sutton R, Sia KC, Evans K, Richmond J, Law T, Venn NC, Irving JA, Moore S, Nievergall E, Dang P, Heatley SL, White DL, and Revesz T
- Subjects
- Animals, Bone Marrow Transplantation, Child, Preschool, Female, Heterografts, Humans, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Recurrence, Precision Medicine methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Published
- 2016
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35. Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia.
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Irving JA, Enshaei A, Parker CA, Sutton R, Kuiper RP, Erhorn A, Minto L, Venn NC, Law T, Yu J, Schwab C, Davies R, Matheson E, Davies A, Sonneveld E, den Boer ML, Love SB, Harrison CJ, Hoogerbrugge PM, Revesz T, Saha V, and Moorman AV
- Subjects
- Adolescent, Child, Child, Preschool, Chromosome Aberrations, Cohort Studies, Cytogenetic Analysis, DNA Copy Number Variations genetics, Demography, Disease-Free Survival, Female, Humans, Infant, Male, Mutation genetics, Prognosis, Recurrence, Risk Factors, Genetic Predisposition to Disease, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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36. COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia.
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Lopes BA, Meyer C, Barbosa TC, Zur Stadt U, Horstmann M, Venn NC, Heatley S, White DL, Sutton R, Pombo-de-Oliveira MS, Marschalek R, and Emerenciano M
- Subjects
- Adolescent, Amino Acid Sequence, Base Sequence, Child, Preschool, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, Pair 7 genetics, DNA Copy Number Variations, Female, Humans, Infant, Isochromosomes genetics, Male, Nucleic Acid Amplification Techniques methods, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Gene Deletion, Ikaros Transcription Factor genetics, Microfilament Proteins genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2-8, Δ3-8 or Δ4-8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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37. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
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Andersson AK, Ma J, Wang J, Chen X, Gedman AL, Dang J, Nakitandwe J, Holmfeldt L, Parker M, Easton J, Huether R, Kriwacki R, Rusch M, Wu G, Li Y, Mulder H, Raimondi S, Pounds S, Kang G, Shi L, Becksfort J, Gupta P, Payne-Turner D, Vadodaria B, Boggs K, Yergeau D, Manne J, Song G, Edmonson M, Nagahawatte P, Wei L, Cheng C, Pei D, Sutton R, Venn NC, Chetcuti A, Rush A, Catchpoole D, Heldrup J, Fioretos T, Lu C, Ding L, Pui CH, Shurtleff S, Mullighan CG, Mardis ER, Wilson RK, Gruber TA, Zhang J, and Downing JR
- Subjects
- Allelic Imbalance genetics, Cohort Studies, DNA Mutational Analysis, Gene Frequency, Histone-Lysine N-Methyltransferase, Humans, Infant, Oncogene Proteins, Fusion genetics, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Signal Transduction genetics, ras Proteins genetics, ras Proteins metabolism, Mutation, Myeloid-Lymphoid Leukemia Protein genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.
- Published
- 2015
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38. Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia.
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Richmond J, Carol H, Evans K, High L, Mendomo A, Robbins A, Meyer C, Venn NC, Marschalek R, Henderson M, Sutton R, Kurmasheva RT, Kees UR, Houghton PJ, Smith MA, and Lock RB
- Subjects
- Animals, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cyclin A1 biosynthesis, Female, Histone-Lysine N-Methyltransferase genetics, Homeodomain Proteins biosynthesis, Humans, Infant, Jurkat Cells, Mice, Mice, Inbred NOD, Mice, SCID, Myeloid Ecotropic Viral Integration Site 1 Protein, Myeloid-Lymphoid Leukemia Protein genetics, Neoplasm Proteins biosynthesis, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Tumor Suppressor Protein p53 genetics, Xenograft Model Antitumor Assays, Imidazolines therapeutic use, Leukemia, Biphenotypic, Acute drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Proto-Oncogene Proteins c-mdm2 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts., Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated., Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft., Conclusions: The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation., (©2015 American Association for Cancer Research.)
- Published
- 2015
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39. Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia.
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Sutton R, Shaw PJ, Venn NC, Law T, Dissanayake A, Kilo T, Haber M, Norris MD, Fraser C, Alvaro F, Revesz T, Trahair TN, Dalla-Pozza L, Marshall GM, and O'Brien TA
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Child, Combined Modality Therapy, Female, Gene Deletion, Humans, Ikaros Transcription Factor genetics, Kaplan-Meier Estimate, Male, Neoplasm Proteins genetics, Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Recurrence, Transplantation Conditioning methods, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0·0001) or post-HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2015
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40. The MLL recombinome of acute leukemias in 2013.
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Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Emerenciano M, Pombo de Oliveira M, Renneville A, Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Vormoor J, Choi WW, Jarosova M, Kolenova A, Bueno C, Menendez P, Wehner S, Eckert C, Talmant P, Tondeur S, Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, Callanan MB, Cayuela JM, Herbaux C, Cazzaniga G, Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre P, Te Kronnie G, Schäfer BW, Kubetzko S, Alonso CN, zur Stadt U, Sutton R, Venn NC, Izraeli S, Trakhtenbrot L, Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke A, Stanulla M, Schrappe M, Sedék L, Szczepański T, Zwaan CM, Coenen EA, van den Heuvel-Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, and Marschalek R
- Subjects
- Acute Disease, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Animals, Child, Child, Preschool, Female, Histone-Lysine N-Methyltransferase, Humans, Infant, Infant, Newborn, Leukemia classification, Male, Mice, Middle Aged, Polymerase Chain Reaction, Prognosis, Young Adult, Chromosome Breakage, Gene Rearrangement, Leukemia genetics, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Proteins, Fusion genetics, Translocation, Genetic genetics
- Abstract
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
- Published
- 2013
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41. Improving the identification of high risk precursor B acute lymphoblastic leukemia patients with earlier quantification of minimal residual disease.
- Author
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Karsa M, Dalla Pozza L, Venn NC, Law T, Shi R, Giles JE, Bahar AY, Cross S, Catchpoole D, Haber M, Marshall GM, Norris MD, and Sutton R
- Subjects
- Child, Cohort Studies, Female, Humans, Male, Neoplasm, Residual pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Recurrence, Risk Factors, Neoplasm, Residual diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis
- Abstract
The stratification of patients with acute lymphoblastic leukemia (ALL) into treatment risk groups based on quantification of minimal residual disease (MRD) after induction therapy is now well accepted but the relapse rate of about 20% in intermediate risk patients remains a challenge. The purpose of this study was to further improve stratification by MRD measurement at an earlier stage. MRD was measured in stored day 15 bone marrow samples for pediatric patients enrolled on ANZCHOG ALL8 using Real-time Quantitative PCR to detect immunoglobulin and T-cell receptor gene rearrangements with the same assays used at day 33 and day 79 in the original MRD stratification. MRD levels in bone marrow at day 15 and 33 were highly predictive of outcome in 223 precursor B-ALL patients (log rank Mantel-Cox tests both P<0.001) and identified patients with poor, intermediate and very good outcomes. The combined use of MRD at day 15 (≥ 1 × 10(-2)) and day 33 (≥ 5 × 1(-5)) identified a subgroup of medium risk precursor B-ALL patients as poor MRD responders with 5 year relapse-free survival of 55% compared to 84% for other medium risk patients (log rank Mantel-Cox test, P = 0.0005). Risk stratification of precursor B-ALL but not T-ALL could be improved by using MRD measurement at day 15 and day 33 instead of day 33 and day 79 in similar BFM-based protocols for children with this disease.
- Published
- 2013
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42. High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation.
- Author
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Marshall GM, Dalla Pozza L, Sutton R, Ng A, de Groot-Kruseman HA, van der Velden VH, Venn NC, van den Berg H, de Bont ES, Maarten Egeler R, Hoogerbrugge PM, Kaspers GJ, Bierings MB, van der Schoot E, van Dongen J, Law T, Cross S, Mueller H, de Haas V, Haber M, Révész T, Alvaro F, Suppiah R, Norris MD, and Pieters R
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols adverse effects, Asparaginase administration & dosage, Asparaginase adverse effects, Child, Child, Preschool, Combined Modality Therapy, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Female, Humans, Infant, Kaplan-Meier Estimate, Male, Mercaptopurine administration & dosage, Mercaptopurine adverse effects, Methotrexate administration & dosage, Methotrexate adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Prednisone administration & dosage, Prednisone adverse effects, Prospective Studies, Remission Induction, Risk Factors, Transplantation, Homologous, Treatment Outcome, Vincristine administration & dosage, Vincristine adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.
- Published
- 2013
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43. Isolated testicular relapse after allo-SCT in boys with ALL: outcome without second transplant.
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Bhadri VA, McGregor MR, Venn NC, Hackenberg N, Russell SJ, Norris MD, Haber M, Sutton R, and Marshall GM
- Subjects
- Bone Marrow Diseases etiology, Child, Child, Preschool, Humans, Male, Neoplasm, Residual, Recurrence, Transplantation, Homologous, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Stem Cell Transplantation adverse effects, Testicular Neoplasms etiology
- Published
- 2010
- Full Text
- View/download PDF
44. Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia.
- Author
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Sutton R, Venn NC, Tolisano J, Bahar AY, Giles JE, Ashton LJ, Teague L, Rigutto G, Waters K, Marshall GM, Haber M, and Norris MD
- Subjects
- Adolescent, Case-Control Studies, Child, Child, Preschool, Combined Modality Therapy, Disease-Free Survival, Female, Humans, Infant, Male, Neoplasm, Residual, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma radiotherapy, Recurrence, Risk Factors, Time Factors, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Detection of minimal residual disease (MRD) after induction and consolidation therapy is highly predictive of outcome for childhood acute lymphoblastic leukaemia (ALL) and is used to identify patients at high risk of relapse in several current clinical trials. To evaluate the prognostic significance of MRD at other treatment phases, MRD was measured by real-time quantitative polymerase chain reaction on a selected group of 108 patients enrolled on the Australian and New Zealand Children's Cancer Study Group Study VII including 36 patients with a bone marrow or central nervous system relapse and 72 matched patients in first remission. MRD was prognostic of outcome at all five treatment phases tested: at day 15 (MRD > or = 5 x 10(-2), log rank P < 0.0001), day 35 (> or =1 x 10(-2), P = 0.0001), 4 months (> or =5 x 10(-4), P < 0.0001), 12 months (MRD > or = 1 x 10(-4), P = 0.006) and 24 months (MRD > or = 1 x 10(-4), P < 0.0001). Day 15 was the best early MRD time-point to differentiate between patients with high, intermediate and low risk of relapse. MRD testing at 12 and particularly at 24 months, detected molecular relapses in some patients up to 6 months before clinical relapse. This raised the question of whether a strategy of late monitoring and salvage therapy will improve outcome.
- Published
- 2009
- Full Text
- View/download PDF
45. Determining the repertoire of IGH gene rearrangements to develop molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia.
- Author
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Brisco MJ, Latham S, Sutton R, Hughes E, Wilczek V, van Zanten K, Budgen B, Bahar AY, Malec M, Sykes PJ, Kuss BJ, Waters K, Venn NC, Giles JE, Haber M, Norris MD, Marshall GM, and Morley AA
- Subjects
- Adult, Child, Cooperative Behavior, DNA, Neoplasm genetics, Genetic Markers, Genome, Human genetics, Humans, Neoplasm, Residual genetics, Cell Lineage, Gene Rearrangement, B-Lymphocyte, Immunoglobulin Heavy Chains genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia were identified by determining, at the time of diagnosis, the repertoire of rearrangements of the immunoglobulin heavy chain (IGH) gene using segment-specific variable (V), diversity (D), and junctional (J) primers in two different studies that involved a total study population of 75 children and 18 adults. This strategy, termed repertoire analysis, was compared with the conventional strategy of identifying markers using family-specific V, D, and J primers for a variety of antigen receptor genes. Repertoire analysis detected significantly more markers for the major leukemic clone than did the conventional strategy, and one or more IgH rearrangements that were suitable for monitoring the major clone were detected in 96% of children and 94% of adults. Repertoire analysis also detected significantly more IGH markers for minor clones. Some minor clones were quite large and a proportion of them would not be able to be detected by a minimal residual disease test directed to the marker for the major clone. IGH repertoire analysis at diagnosis has potential advantages for the identification of molecular markers for the quantification of minimal residual disease in acute lymphoblastic leukemia cases. An IGH marker enables very sensitive quantification of the major leukemic clone, and the detection of minor clones may enable early identification of additional patients who are prone to relapse.
- Published
- 2009
- Full Text
- View/download PDF
46. Sensitive and specific measurement of minimal residual disease in acute lymphoblastic leukemia.
- Author
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Morley AA, Latham S, Brisco MJ, Sykes PJ, Sutton R, Hughes E, Wilczek V, Budgen B, van Zanten K, Kuss BJ, Venn NC, Norris MD, Crock C, Storey C, Revesz T, and Waters K
- Subjects
- Child, DNA, Neoplasm analysis, Fluorescence, Humans, Neoplasm, Residual, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Sensitivity and Specificity, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
A sensitive and specific quantitative real-time polymerase chain reaction method, involving three rounds of amplification with two allele-specific oligonucleotide primers directed against an rearrangement, was developed to quantify minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL). For a single sample containing 10 microg of good quality DNA, MRD was quantifiable down to approximately 10(-6), which is at least 1 log more sensitive than current methods. Nonspecific amplification was rarely observed. The standard deviation of laboratory estimations was 0.32 log units at moderate or high levels of MRD, but increased markedly as the level of MRD and the number of intact marker gene rearrangements in the sample fell. In 23 children with ALL studied after induction therapy, the mean MRD level was 1.6 x 10(-5) and levels ranged from 1.5 x 10(-2) to less than 10(-7). Comparisons with the conventional one-round quantitative polymerase chain reaction method on 29 samples from another 24 children who received treatment resulted in concordant results for 22 samples and discordant results for seven samples. The sensitivity and specificity of the method are due to the use of nested polymerase chain reaction, one segment-specific and two allele-specific oligonucleotide primers, and the use of a large amount of good quality DNA. This method may improve MRD-based decisions on treatment for ALL patients, and the principles should be applicable to DNA-based MRD measurements in other disorders.
- Published
- 2009
- Full Text
- View/download PDF
47. Improving minimal residual disease detection in precursor B-ALL based on immunoglobulin-kappa and heavy-chain gene rearrangements.
- Author
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Sutton R, Bahar AY, Kwan E, Giles JE, Venn NC, Tran S, Hackenberg N, Pozza LD, Marshall GM, Haber M, van der Velden VH, and Norris MD
- Subjects
- Child, Gene Rearrangement, B-Lymphocyte genetics, Genetic Markers, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin kappa-Chains genetics, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2008
- Full Text
- View/download PDF
48. Two cases of hypereosinophilia and high-risk acute lymphoblastic leukemia.
- Author
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Sutton R, Lonergan M, Tapp H, Venn NC, Haber M, Norris MD, O'Brien TA, Alvaro F, and Revesz T
- Subjects
- Child, Female, Humans, Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Hypereosinophilic Syndrome etiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications
- Published
- 2008
- Full Text
- View/download PDF
49. Mechanism of relapse in pediatric acute lymphoblastic leukemia.
- Author
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Henderson MJ, Choi S, Beesley AH, Sutton R, Venn NC, Marshall GM, Kees UR, Haber M, and Norris MD
- Subjects
- Child, Genetic Markers genetics, Humans, Models, Biological, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Receptors, Antigen genetics, Recurrence, Time Factors, Drug Resistance, Neoplasm, Gene Rearrangement genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma prevention & control
- Abstract
Relapse following initial chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). Recently, to investigate the mechanism of relapse, we analysed clonal populations in 27 pairs of matched diagnosis and relapse ALL samples using PCR-based detection of multiple antigen receptor gene rearrangements. These clonal markers revealed the emergence of apparently new populations at relapse in 13 patients. In those cases where the new 'relapse clone' could be detected in the diagnosis population, there was a close correlation between length of first remission and quantity of the relapse clone in the diagnosis sample. A shorter length of time to first relapse correlated with a higher quantity of the relapsing clone at diagnosis. This observation, together with demonstrated differential chemosensitivity between sub-clones at diagnosis, indicates that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant sub-clone that is undetectable by routine PCR-based methods. From a clinical perspective, relapse prediction may be improved with strategies to detect minor potentially resistant sub-clones early during treatment, hence allowing intensification of therapy. Together with the availability of relevant in vivo experimental models and powerful technology for detailed analysis of patient specimens, this new information will help shape future experimentation towards targeted therapy for high-risk ALL.
- Published
- 2008
- Full Text
- View/download PDF
50. Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone.
- Author
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Choi S, Henderson MJ, Kwan E, Beesley AH, Sutton R, Bahar AY, Giles J, Venn NC, Pozza LD, Baker DL, Marshall GM, Kees UR, Haber M, and Norris MD
- Subjects
- Age of Onset, B-Lymphocytes immunology, Child, Preschool, Clone Cells, Female, Gene Rearrangement, Humans, Immunoglobulins blood, Immunophenotyping, Infant, Male, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Receptors, Antigen genetics, Recurrence, Drug Resistance, Neoplasm, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Relapse following remission induction chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). To investigate the mechanism of relapse, 27 matched diagnosis and relapse ALL samples were analyzed for clonal populations using polymerase chain reaction (PCR)-based detection of multiple antigen receptor gene rearrangements. These clonal markers revealed the emergence of apparently new populations at relapse in 13 patients. More sensitive clone-specific PCR revealed that, in 8 cases, these "relapse clones" were present at diagnosis and a significant relationship existed between presence of the relapse clone at diagnosis and time to first relapse (P < .007). Furthermore, in cases where the relapse clone could be quantified, time to first relapse was dependent on the amount of the relapse clone at diagnosis (r = -0.84; P = .018). This observation, together with demonstrated differential chemosensitivity between subclones at diagnosis, argues against therapy-induced acquired resistance as the mechanism of relapse in the informative patients. Instead these data indicate that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant subclone that is undetectable by routine PCR-based methods. Relapse prediction may be improved with strategies to detect minor potentially resistant subclones early during treatment, hence allowing intensification of therapy.
- Published
- 2007
- Full Text
- View/download PDF
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