108 results on '"Roti, G"'
Search Results
2. 238P Exploring blood immune cell dynamics to unravel the immunomodulatory effect of radiotherapy in NSCLC patients undergoing immune checkpoint inhibitors
- Author
-
Mazzaschi, G., Tamarozzi, P., Lorusso, B., Verzè, M., Pluchino, M., Trentini, F., Dalla Valle, B., Minari, R., Perrone, F., Bordi, P., Leonetti, A., Moron Dalla Tor, L., Leo, L., Milanese, G., Balbi, M., Buti, S., Roti, G., Quaini, F., Sverzellati, N., and Tiseo, M.
- Published
- 2022
- Full Text
- View/download PDF
3. 2315P Clinical and blood immune-inflammatory profiling to decode different patterns of acquired resistance in immunotherapy treated NSCLC patients
- Author
-
Mazzaschi, G., Cardinale, E., Pluchino, M., Monica, G., Lorusso, B., D'Agnelli, S., Trentini, F., Tamarozzi, P., Dalla Tor, L. Moron, Verzè, M., Minari, R., Bordi, P., Perrone, F., Leonetti, A., Gnetti, L., Roti, G., Quaini, F., Sverzellati, N., and Tiseo, M.
- Published
- 2023
- Full Text
- View/download PDF
4. Different genomic imbalances in low- and high-grade HCV-related lymphomas
- Author
-
Matteucci, C, Bracci, M, Barba, G, Carbonari, M, Casato, M, Visentini, M, Pulsoni, A, Varasano, E, Roti, G, Starza, R La, Crescenzi, B, Martelli, M F, Fiorilli, M, and Mecucci, C
- Published
- 2008
- Full Text
- View/download PDF
5. A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan Syndrome
- Author
-
La Starza, R, Rosati, R, Roti, G, Gorello, P, Bardi, A, Crescenzi, B, Pierini, V, Calabrese, O, Baens, M, Folens, C, Cools, J, Marynen, P, Martelli, M F, Mecucci, C, and Cuneo, A
- Published
- 2007
- Full Text
- View/download PDF
6. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations
- Author
-
Gorello, P, Cazzaniga, G, Alberti, F, Dell'Oro, M G, Gottardi, E, Specchia, G, Roti, G, Rosati, R, Martelli, M F, Diverio, D, Coco, F Lo, Biondi, A, Saglio, G, Mecucci, C, and Falini, B
- Published
- 2006
- Full Text
- View/download PDF
7. 189P The parallel interrogation of tissue and peripheral blood immune features unveils a bidirectional crosstalk with clinical impact on resected NSCLC
- Author
-
Mazzaschi, G., Bocchialini, G., Lorusso, B., Pluchino, M., Trentini, F., Di Rienzo, G., Cattadori, S., Tor, L. Moron Dalla, Verzè, M., Minari, R., Bordi, P., Leonetti, A., D’Agnelli, S., Milanese, G., Leo, L., Gnetti, L., Roti, G., Ampollini, L., Quaini, F., Sverzellati, N., and Tiseo, M.
- Published
- 2023
- Full Text
- View/download PDF
8. 1061P Static and dynamic tracking of radiomic and immunophenotypic features predicts the benefit of immune checkpoint inhibitors in advanced NSCLC
- Author
-
Mazzaschi, G., Moron Dalla Tor, L., Balbi, M., Milanese, G., Tognazzi, D., Lorusso, B., Trentini, F., Di Rienzo, G., Verzè, M., Pluchino, M., Minari, R., Leo, L., Gnetti, L., Bordi, P., Leonetti, A., Ampollini, L., Roti, G., Quaini, F., Sverzellati, N., and Tiseo, M.
- Published
- 2022
- Full Text
- View/download PDF
9. BEPRIDIL IS A POTENT NOTCH1 INHIBITOR AND EFFICIENTLY INDUCES APOPTOSIS IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) CELLS in vitro AND in vivo
- Author
-
Baldoni, S, Del Papa, B, Aureli, P, Dorillo, E, Varasano, E, Zei, T, Iacucci, R, Cecchini, D, Di Tommaso, A, De Falco, F, Plebani, S, Roti, G, Stegmaier, K, Rosati, E, Di Ianni, M, Falzetti, F, and Sportoletti, P
- Published
- 2016
10. 1982PD - Identification of a radio-immune signature with high prognostic value in surgically resected NSCLC
- Author
-
Mazzaschi, G., Quaini, F., Milanese, G., Gnetti, L., Bocchialini, G., Ampollini, L., Minari, R., Silva, M., Sverzellati, N., Roti, G., and Tiseo, M.
- Published
- 2019
- Full Text
- View/download PDF
11. 1O - Advanced CT imaging features reflect distinct tissue immune profiles and exhibit high prognostic impact on NSCLC
- Author
-
Mazzaschi, G., Pagano, P., Milanese, G., Madeddu, D., Falco, A., Armani, G., Bocchialini, G., Marturano, D., Ampollini, L., Lorusso, B., Lagrasta, C., Sverzellati, N., Silva, M., Tiseo, M., Quaini, F., and Roti, G.
- Published
- 2018
- Full Text
- View/download PDF
12. P1.15-04 Dynamic Profiling of Blood Immunophenotypes and Radiomic Features to Predict Immunotherapy Response in Advanced Non-small Cell Lung Cancer.
- Author
-
Mazzaschi, G., Moron Dalla Tor, L., Milanese, G., Balbi, M., Tognazzi, D., Lorusso, B., Verzè, M., Pluchino, M., Minari, R., Leo, L., Ledda, R.E., Bordi, P., Leonetti, A., Buti, S., Roti, G., Quaini, F., Sverzellati, N., and Tiseo, M.
- Published
- 2022
- Full Text
- View/download PDF
13. P336: A CHEMOTRANSCRIPTOMIC SCREENING IDENTIFIES THE REVERSAL OF GLUCOCORTICOID RESISTANCE IN NOTCH1 MUTATED T‐ALL.
- Author
-
Pagliaro, L., Moron Dalla Tor, L., Federica, V., Andrei, P., Monica, L., Kleissle, S., Neuenschwander, M., Gherli, A., Cerretani, E., D'Antuono, A., Simoncini, E., Montanaro, A., and Roti, G.
- Published
- 2022
- Full Text
- View/download PDF
14. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acutemyeloid leukemia
- Author
-
Falini, B, Martelli, Mp, Bolli, N, Bonasso, R, Ghia, E, Pallotta, Mt, Diverio, D, Nicoletti, I, Pacini, R, Tabarrini, A, Galletti, Bv, Mannucci, R, Roti, G, Rosati, R, Specchia, G, Liso, A, Tiacci, E, Alcalay, M, Luzi, L, Volorio, S, Bernard, L, Guarini, A, Amadori, S, Mandelli, F, Pane, F, Lo Coco, F, Saglio, Giuseppe, Pelicci, Pg, Martelli, Mf, and Mecucci, C.
- Published
- 2006
15. Quantitative assessment of minimal residual disease in acute myeloidleukemia carrying nucleophosmin (NPM1) gene mutations
- Author
-
Gorello, P, Cazzaniga, G, Alberti, F, Dell'Oro, Mg, Gottardi, E, Specchia, G, Roti, G, Rosati, R, Martelli, Mf, Diverio, D, Lo Coco, F, Biondi, A, Saglio, Giuseppe, Mecucci, C, and Falini, B.
- Published
- 2006
16. Genetic and proteomic approaches to identify cancer drug targets.
- Author
-
Roti, G and Stegmaier, K
- Subjects
- *
CHEMOGENOMICS , *PROTEOMICS , *DRUG development , *CANCER treatment , *GENE expression - Abstract
While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
17. C022 NPM1 monoallelic deletion in a subgroup of MDS/AML with del (5q) or monosomy 5 and complex karyotype
- Author
-
La Starza, R., Roti, G., Brandimarte, L., Varasano, E., Arcioni, F., Pierini, A., Crescenzi, B., Diverio, D., Guglielmini, G., Martelli, M.F., Aventin, A., and Mecucci, C.
- Published
- 2007
- Full Text
- View/download PDF
18. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia
- Author
-
Jan Cools, Martina Moretti, Peter Vandenberghe, Paolo Gorello, Giovanni Roti, Renato Bassan, Giovanna De Santis, Rocco Piazza, Nicoletta Testoni, Fabrizia Pellanera, Roberta La Starza, Jean-Pierre Bourquin, Cristina Mecucci, Kim De Keersmaecker, Zeynep Kalender Atak, Christine J. Harrison, Valentina Pierini, Beat Bornhauser, Danika Di Giacomo, Caterina Matteucci, Silvia Arniani, Stein Aerts, Di Giacomo, D, La Starza, R, Gorello, P, Pellanera, F, Kalender Atak, Z, De Keersmaecker, K, Pierini, V, Harrison, C, Arniani, S, Moretti, M, Testoni, N, De Santis, G, Roti, G, Matteucci, C, Bassan, R, Vandenberghe, P, Aerts, S, Cools, J, Bornhauser, B, Bourquin, J, Piazza, R, Mecucci, C, University of Zurich, Mecucci, Cristina, Di Giacomo D., La Starza R., Gorello P., Pellanera F., Kalender Atak Z., De Keersmaecker K., Pierini V., Harrison C.J., Arniani S., Moretti M., Testoni N., De Santis G., Roti G., Matteucci C., Bassan R., Vandenberghe P., Aerts S., Cools J., Bornhauser B., Bourquin J.-P., Piazza R., and Mecucci C.
- Subjects
Adult ,Male ,Myeloid ,1303 Biochemistry ,Adolescent ,BCL11B ,Immunology ,2720 Hematology ,Chromosomal translocation ,610 Medicine & health ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Biochemistry ,Translocation, Genetic ,Fusion gene ,1307 Cell Biology ,hemic and lymphatic diseases ,Acute lymphocytic leukemia ,medicine ,Biomarkers, Tumor ,Humans ,Child ,Aged ,Chromosomes, Human, Pair 14 ,Acute leukemia ,2403 Immunology ,Tumor Suppressor Protein ,Gene Expression Regulation, Leukemic ,Tumor Suppressor Proteins ,Gene Expression Profiling ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Repressor Protein ,medicine.disease ,Repressor Proteins ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Fusion transcript ,10036 Medical Clinic ,Child, Preschool ,Cancer research ,Female ,Human - Abstract
Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.
- Published
- 2021
19. 17P Dynamic changes of CT-radiomic and systemic immune-inflammatory features predict the response to immune checkpoint inhibitors in advanced NSCLC patients.
- Author
-
Mazzaschi, G., Milanese, G., Moron Dalla Tor, L., Leo, L., Balbi, M., Trentini, F., Manini, M., Pavone, C., Silva, M., Ledda, R.E., Minari, R., Bordi, P., Buti, S., Leonetti, A., Roti, G., Quaini, F., Sverzellati, N., and Tiseo, M.
- Subjects
- *
IMMUNE checkpoint inhibitors , *IMMUNE response , *NON-small-cell lung carcinoma - Published
- 2021
- Full Text
- View/download PDF
20. The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia.
- Author
-
Banerji V, Frumm SM, Ross KN, Li LS, Schinzel AC, Hahn CK, Kakoza RM, Chow KT, Ross L, Alexe G, Tolliday N, Inguilizian H, Galinsky I, Stone RM, DeAngelo DJ, Roti G, Aster JC, Hahn WC, Kung AL, and Stegmaier K
- Abstract
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
21. A Distinct Epigenetic Program Underlies the 1;7 Translocation in Myelodysplastic Syndromes
- Author
-
Barbara Crescenzi, Danika Di Giacomo, Valentina Pierini, Valeria Di Battista, Cristina Mecucci, Emmalee R. Adelman, Rocco Piazza, Fabrizia Pellanera, Giovanni Roti, Gianluca Barba, Maria E. Figueroa, Anair Graciela Lema Fernandez, Fernandez, A, Crescenzi, B, Pierini, V, Di Battista, V, Barba, G, Pellanera, F, Di Giacomo, D, Roti, G, Piazza, R, Adelman, E, Figueroa, M, and Mecucci, C
- Subjects
0301 basic medicine ,Adult ,Epigenomics ,Male ,Cancer Research ,Epigenomic ,Transcription, Genetic ,Myelodysplastic Syndrome ,Down-Regulation ,Chromosomal translocation ,Chromosome Disorders ,Trisomy ,Biology ,Article ,Translocation, Genetic ,Epigenesis, Genetic ,03 medical and health sciences ,Dicentric chromosome ,0302 clinical medicine ,Monosomy ,Retrospective Studie ,hemic and lymphatic diseases ,medicine ,80 and over ,Humans ,Epigenetics ,Enhancer ,Gene ,Aged ,Retrospective Studies ,Genetics ,Aged, 80 and over ,Binding Sites ,Binding Site ,Hematology ,Middle Aged ,medicine.disease ,030104 developmental biology ,Chromosome Disorder ,Oncology ,030220 oncology & carcinogenesis ,Karyotyping ,Myelodysplastic Syndromes ,DNA methylation ,Female ,Human - Abstract
The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Kruppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.
- Published
- 2019
22. Cytoplasmic nucleophosmin in myeloid sarcoma occurring 20 years after diagnosis of acute myeloid leukaemia.
- Author
-
Bolli N, Galimberti S, Martelli MP, Tabarrini A, Roti G, Mecucci C, Martelli MF, Petrini M, and Falini B
- Subjects
- *
MYELOID leukemia genetics , *GENETIC mutation , *TIME , *MYELOID leukemia , *SKIN tumors , *SECONDARY primary cancer , *SARCOMA , *ACUTE diseases - Published
- 2006
- Full Text
- View/download PDF
23. 2O Differentially regulated high-throughput CT imaging features correlate to distinct tumor immune contextures portraying a radiomic signature with prognostic impact on surgically resected NSCLC.
- Author
-
Mazzaschi, G, Quaini, F, Milanese, G, Madeddu, D, Bocchialini, G, Ampollini, L, Gnetti, L, Lagrasta, C, Silva, M, Roti, G, Sverzellati, N, and Tiseo, M
- Subjects
- *
ACADEMIC medical centers , *NON-small-cell lung carcinoma , *TUMORS , *BONE marrow transplantation , *UNIVERSITY hospitals - Published
- 2019
- Full Text
- View/download PDF
24. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML
- Author
-
Alessandra Pucciarini, Wei Gu, Giovanni Roti, Maria Paola Martelli, Roberto Rosati, Laura Pasqualucci, Torsten Haferlach, Barbara Bigerna, Brunangelo Falini, Suzanne Schnittger, Giovanni Cazzaniga, Enrico Tiacci, Cristina Mecucci, Roberta Mannucci, Jing Shan, Andrea Biondi, Massimo F. Martelli, Paolo Gorello, Wolfgang Hiddemann, Daniela Diverio, Niccolo Bolli, Ildo Nicoletti, Arcangelo Liso, Falini, B, Bolli, N, Shan, J, Martelli, M, Liso, A, Pucciarini, A, Bigerna, B, Pasqualucci, L, Mannucci, R, Rosati, R, Gorello, P, Diverio, D, Roti, G, Tiacci, E, Cazzaniga, G, Biondi, A, Schnittger, S, Haferlach, T, Hiddemann, W, Gu, W, Mecucci, C, and Nicoletti, I
- Subjects
Cytoplasm ,Nucleolus ,Immunology ,Mutant ,Amino Acid Motifs ,Active Transport, Cell Nucleus ,Biology ,Transfection ,Biochemistry ,Cell Line ,medicine ,Animals ,Humans ,Nuclear protein ,Nuclear export signal ,Nuclear Protein ,Nuclear Export Signals ,Nucleophosmin ,Nucleoplasm ,Leukemia ,integumentary system ,Base Sequence ,Animal ,Active Transport, Cell Nucleu ,Tryptophan ,Nuclear Proteins ,Cell Biology ,Hematology ,Nuclear Export Signal ,Cell biology ,Cell nucleus ,medicine.anatomical_structure ,Cell Nucleolu ,Mutation ,Amino Acid Motif ,Cell Nucleolus ,Human - Abstract
We recently identified aberrant cytoplasmic expression of nucleophosmin (NPM) as the immunohistochemical marker of a large subgroup of acute myeloid leukemia (AML) (about one-third of adult AML) that is characterized by normal karyotype and mutations occurring at the exon-12 of the NPM gene. In this paper, we have elucidated the molecular mechanism underlying the abnormal cytoplasmic localization of NPM. All 29 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal (NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm. In fact, the cytoplasmic accumulation of NPM is blocked by leptomycin-B and ratjadones, specific exportin-1/Crm1-inhibitors, and by reinsertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. NPM leukemic mutants in turn recruit the wild-type NPM from nucleoli to nucleoplasm and cytoplasm. These findings indicate that potential therapeutic strategies aimed to retarget NPM to its physiological sites will have to overcome 2 obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutant C-terminus.
- Published
- 2006
25. Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.
- Author
-
Mosna F, Borlenghi E, Litzow M, Byrd JC, Papayannidis C, Tecchio C, Ferrara F, Marcucci G, Cairoli R, Morgan EA, Gurrieri C, Yeung CCS, Deeg HJ, Capelli D, Candoni A, Gotlib JR, Lunghi M, Pullarkat S, Lanza F, Galimberti S, Forghieri F, Venditti A, Festuccia M, Audisio E, Marvalle D, Rigolin GM, Roti G, DiBona E, Visani G, Albano F, Eisfeld AK, Valent P, Huls G, Borthakur G, Krampera M, Martinelli G, Kröger N, Sperotto A, and Gottardi M
- Abstract
Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.
- Published
- 2024
- Full Text
- View/download PDF
26. Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line.
- Author
-
Guidetti L, Castelli R, Zappia A, Ferrari FR, Giorgio C, Barocelli E, Pagliaro L, Vento F, Roti G, Scalvini L, Vacondio F, Rivara S, Mor M, Lodola A, and Tognolini M
- Subjects
- Humans, Cell Line, Tumor, Dose-Response Relationship, Drug, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Hydrocarbons, Fluorinated chemical synthesis, Hydrocarbons, Fluorinated chemistry, Hydrocarbons, Fluorinated pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Drug Discovery, Drug Screening Assays, Antitumor, Glioblastoma drug therapy, Glioblastoma pathology, Glioblastoma metabolism, Indoles pharmacology, Indoles chemistry, Indoles chemical synthesis, Receptor, EphA2 antagonists & inhibitors, Receptor, EphA2 metabolism
- Abstract
In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-β-homotryptophan conjugates of 3-β-hydroxy-Δ
5 -cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Massimiliano Tognolini reports financial support was provided by Italian Association for Cancer Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
27. CD26 Is Differentially Expressed throughout the Life Cycle of Infantile Hemangiomas and Characterizes the Proliferative Phase.
- Author
-
Lorusso B, Nogara A, Fioretzaki R, Corradini E, Bove R, Roti G, Gherli A, Montanaro A, Monica G, Cavazzini F, Bonomini S, Graiani G, Silini EM, Gnetti L, Pilato FP, Cerasoli G, Quaini F, and Lagrasta CAM
- Subjects
- Humans, Infant, Female, Male, Child, Preschool, Endothelial Cells metabolism, Endothelial Cells pathology, Nestin metabolism, Nestin genetics, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Child, WT1 Proteins metabolism, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Ki-67 Antigen metabolism, Glucose Transporter Type 1 metabolism, Glucose Transporter Type 1 genetics, Infant, Newborn, Dipeptidyl Peptidase 4 metabolism, Dipeptidyl Peptidase 4 genetics, Hemangioma metabolism, Hemangioma pathology, Cell Proliferation, Vildagliptin pharmacology, AC133 Antigen metabolism
- Abstract
Infantile hemangiomas (IHs) are benign vascular neoplasms of childhood (prevalence 5-10%) due to the abnormal proliferation of endothelial cells. IHs are characterized by a peculiar natural life cycle enclosing three phases: proliferative (≤12 months), involuting (≥13 months), and involuted (up to 4-7 years). The mechanisms underlying this neoplastic disease still remain uncovered. Twenty-seven IH tissue specimens (15 proliferative and 12 involuting) were subjected to hematoxylin and eosin staining and a panel of diagnostic markers by immunohistochemistry. WT1, nestin, CD133, and CD26 were also analyzed. Moreover, CD31
pos /CD26pos proliferative hemangioma-derived endothelial cells (Hem-ECs) were freshly isolated, exposed to vildagliptin (a DPP-IV/CD26 inhibitor), and tested for cell survival and proliferation by MTT assay, FACS analysis, and Western blot assay. All IHs displayed positive CD31, GLUT1, WT1, and nestin immunostaining but were negative for D2-40. Increased endothelial cell proliferation in IH samples was documented by ki67 labeling. All endothelia of proliferative IHs were positive for CD26 (100%), while only 10 expressed CD133 (66.6%). Surprisingly, seven involuting IH samples (58.3%) exhibited coexisting proliferative and involuting aspects in the same hemangiomatous lesion. Importantly, proliferative areas were characterized by CD26 immunolabeling, at variance from involuting sites that were always CD26 negative. Finally, in vitro DPP-IV pharmacological inhibition by vildagliptin significantly reduced Hem-ECs proliferation through the modulation of ki67 and induced cell cycle arrest associated with the upregulation of p21 protein expression. Taken together, our findings suggest that CD26 might represent a reliable biomarker to detect proliferative sites and unveil non-regressive IHs after a 12-month life cycle.- Published
- 2024
- Full Text
- View/download PDF
28. End of induction [ 18 F]FDG PET is prognostic for progression-free survival and overall survival in follicular lymphoma patients enrolled in the FOLL12 trial.
- Author
-
Guerra L, Chauvie S, Fallanca F, Bergesio F, Marcheselli L, Durmo R, Peano S, Franceschetto A, Monaco L, Barbieri E, Ladetto M, Musuraca G, Tosi P, Bianchi B, Bolis SAM, Pavone V, Chiarenza A, Arcari A, Califano C, Bari A, Massaia M, Conconi A, Musto P, Mannina D, Roti G, Galimberti S, Gini G, Falcinelli F, Vitolo U, Usai SV, Stefani PM, Ibatici A, Liberati AM, Pennese E, Perrone T, Versari A, and Luminari S
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Adult, Prognosis, Progression-Free Survival, Aged, 80 and over, Radiopharmaceuticals, Lymphoma, Follicular diagnostic imaging, Lymphoma, Follicular therapy, Fluorodeoxyglucose F18, Positron-Emission Tomography
- Abstract
Purpose: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [
18 F]FDG PET (PET) in follicular lymphoma patients., Methods: Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS)., Results: Overall, 807 follicular lymphoma patients-52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3-5)-were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4-5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%-70%). The 5-yr PFS rate for PET neg (DS1-3) and PET pos (DS4-5) patients was 71% (95%CI: 67%-75%) and 36% (95%CI: 25%-46%), respectively, with HR 3.49 (95%CI: 2.57-4.72). Five-year PFS was worse as DS increased, with 74% (70%-78%), 58% (48%-67%; HR 1.71; p = 0.001)] and 36% (25%-46%; HR 3.88; p < 0.001) in DS1-2, DS3 and DS4-5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%-96%), with 96% (95%CI: 94-97) and 82% (95%CI: 72%-89%) in EOI PET negative (DS1-3) and positive (DS4-5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1-2 with high FLIPI-2 (3-5) experienced worse OS than patients with DS1-2 and low FLIPI-2 (1-2) (p = 0.003)., Conclusion: This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1-2 patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
- Full Text
- View/download PDF
29. Longitudinal Changes of CT-radiomic and Systemic Inflammatory Features Predict Survival in Advanced Non-Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors.
- Author
-
Balbi M, Mazzaschi G, Leo L, Moron Dalla Tor L, Milanese G, Marrocchio C, Silva M, Mura R, Favia P, Bocchialini G, Trentini F, Minari R, Ampollini L, Quaini F, Roti G, Tiseo M, and Sverzellati N
- Abstract
Purpose: This study aims to determine whether longitudinal changes in CT radiomic features (RFs) and systemic inflammatory indices outperform single-time-point assessment in predicting survival in advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs)., Materials and Methods: We retrospectively acquired pretreatment (T0) and first disease assessment (T1) RFs and systemic inflammatory indices from a single-center cohort of stage IV NSCLC patients and computed their delta (Δ) variation as [(T1-T0)/T0]. RFs from the primary tumor were selected for building baseline-radiomic (RAD) and Δ-RAD scores using the linear combination of standardized predictors detected by LASSO Cox regression models. Cox models were generated using clinical features alone or combined with baseline and Δ blood parameters and integrated with baseline-RAD and Δ-RAD. All models were 3-fold cross-validated. A prognostic index (PI) of each model was tested to stratify overall survival (OS) through Kaplan-Meier analysis., Results: We included 90 ICI-treated NSCLC patients (median age 70 y [IQR=42 to 85], 63 males). Δ-RAD outperformed baseline-RAD for predicting OS [c-index: 0.632 (95%CI: 0.628 to 0.636) vs. 0.605 (95%CI: 0.601 to 0.608) in the test splits]. Integrating longitudinal changes of systemic inflammatory indices and Δ-RAD with clinical data led to the best model performance [Integrated-Δ model, c-index: 0.750 (95% CI: 0.749 to 0.751) in training and 0.718 (95% CI: 0.715 to 0.721) in testing splits]. PI enabled significant OS stratification within all the models (P-value <0.01), reaching the greatest discriminative ability in Δ models (high-risk group HR up to 7.37, 95% CI: 3.9 to 13.94, P<0.01)., Conclusion: Δ-RAD improved OS prediction compared with single-time-point radiomic in advanced ICI-treated NSCLC. Integrating Δ-RAD with a longitudinal assessment of clinical and laboratory data further improved the prognostic performance., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
30. Bendamustine and rituximab as first-line treatment for symptomatic splenic marginal zone lymphoma: long-term outcome and impact of early unmeasurable minimal residual disease attainment from the BRISMA/IELSG36 phase II study.
- Author
-
Iannitto E, Ferrero S, Bommier C, Drandi D, Ferrante M, Bouabdallah K, Carras S, Gini G, Camus V, Mancuso S, Marcheselli L, Ferrari A, Merli M, Tessoulin B, Stelitano C, Beldjord K, Roti G, Jardin F, Castagnari B, Palombi F, Baseggio L, Traverse-Glehen A, Tripodo C, Liberati AM, Parolini M, Usai S, Patti C, Federico M, Musso M, Ladetto M, Zucca E, and Thieblemont C
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride therapeutic use, Bendamustine Hydrochloride administration & dosage, Lymphoma, B-Cell, Marginal Zone drug therapy, Neoplasm, Residual, Rituximab therapeutic use, Rituximab administration & dosage, Splenic Neoplasms drug therapy
- Published
- 2024
- Full Text
- View/download PDF
31. Acute lymphoblastic leukaemia.
- Author
-
Pagliaro L, Chen SJ, Herranz D, Mecucci C, Harrison CJ, Mullighan CG, Zhang M, Chen Z, Boissel N, Winter SS, and Roti G
- Subjects
- Humans, Genomics, Molecular Targeted Therapy, Quality of Life, Immunotherapy, Adoptive, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma physiopathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Acute lymphoblastic leukaemia (ALL) is a haematological malignancy characterized by the uncontrolled proliferation of immature lymphoid cells. Over past decades, significant progress has been made in understanding the biology of ALL, resulting in remarkable improvements in its diagnosis, treatment and monitoring. Since the advent of chemotherapy, ALL has been the platform to test for innovative approaches applicable to cancer in general. For example, the advent of omics medicine has led to a deeper understanding of the molecular and genetic features that underpin ALL. Innovations in genomic profiling techniques have identified specific genetic alterations and mutations that drive ALL, inspiring new therapies. Targeted agents, such as tyrosine kinase inhibitors and immunotherapies, have shown promising results in subgroups of patients while minimizing adverse effects. Furthermore, the development of chimeric antigen receptor T cell therapy represents a breakthrough in ALL treatment, resulting in remarkable responses and potential long-term remissions. Advances are not limited to treatment modalities alone. Measurable residual disease monitoring and ex vivo drug response profiling screening have provided earlier detection of disease relapse and identification of exceptional responders, enabling clinicians to adjust treatment strategies for individual patients. Decades of supportive and prophylactic care have improved the management of treatment-related complications, enhancing the quality of life for patients with ALL., (© 2024. Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF
32. Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML.
- Author
-
Marchesini M, Gherli A, Simoncini E, Tor LMD, Montanaro A, Thongon N, Vento F, Liverani C, Cerretani E, D'Antuono A, Pagliaro L, Zamponi R, Spadazzi C, Follini E, Cambò B, Giaimo M, Falco A, Sammarelli G, Todaro G, Bonomini S, Adami V, Piazza S, Corbo C, Lorusso B, Mezzasoma F, Lagrasta CAM, Martelli MP, La Starza R, Cuneo A, Aversa F, Mecucci C, Quaini F, Colla S, and Roti G
- Subjects
- Animals, Female, Humans, Mice, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, Gene Expression Regulation, Leukemic drug effects, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-myc genetics, Xenograft Model Antitumor Assays, Chromosomes, Human, Pair 3 genetics, Histone Deacetylase Inhibitors pharmacology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, MDS1 and EVI1 Complex Locus Protein metabolism, MDS1 and EVI1 Complex Locus Protein genetics, Proteogenomics methods
- Abstract
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
33. Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T-cell lymphoblastic leukemia.
- Author
-
Almeida A, T'Sas S, Pagliaro L, Fijalkowski I, Sleeckx W, Van Steenberge H, Zamponi R, Lintermans B, Van Loocke W, Palhais B, Reekmans A, Bardelli V, Demoen L, Reunes L, Deforce D, Van Nieuwerburgh F, Kentsis A, Ntziachristos P, Van Roy N, De Moerloose B, Mecucci C, La Starza R, Roti G, Goossens S, Van Vlierberghe P, and Pieters T
- Abstract
T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for 10%-15% of pediatric and 25% of adult ALL cases. Although the prognosis of T-ALL has improved over time, the outcome of T-ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T-ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto-oncogene MYB is highly expressed in diverse hematologic malignancies, including T-ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T-ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event-free survival of pediatric T-ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB-driven T-ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T-cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T-ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T-ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T-ALL., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)
- Published
- 2024
- Full Text
- View/download PDF
34. CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders.
- Author
-
Pagliaro L, Cerretani E, Vento F, Montanaro A, Moron Dalla Tor L, Simoncini E, Giaimo M, Gherli A, Zamponi R, Tartaglione I, Lorusso B, Scita M, Russo F, Sammarelli G, Todaro G, Silini EM, Rigolin GM, Quaini F, Cuneo A, and Roti G
- Subjects
- Humans, Mutation, Receptor, Notch1 genetics, Hematologic Neoplasms, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca
2+ -ATPase (SERCA) showed a greater effect in NOTCH1 -mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.- Published
- 2024
- Full Text
- View/download PDF
35. Uncovering NOTCH1 as a Promising Target in the Treatment of MLL -Rearranged Leukemia.
- Author
-
Fischer J, Erkner E, Fitzel R, Radszuweit P, Keppeler H, Korkmaz F, Roti G, Lengerke C, Schneidawind D, and Schneidawind C
- Subjects
- Humans, Cell Cycle Checkpoints genetics, Cytarabine therapeutic use, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics, Myeloid-Lymphoid Leukemia Protein metabolism, Oncogene Proteins, Fusion genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Receptor, Notch1 genetics
- Abstract
MLL rearrangement ( MLL r) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 MLL-AF4/-AF9 translocation model, the newly developed NOTCH1 inhibitor CAD204520 with less toxic side effects allowed us to unravel the impact of NOTCH1 as a pathogenic driver and potential therapeutic target in MLL r leukemia. RNA sequencing (RNA-seq) and RT-qPCR of our MLL r model and MLL r cell lines showed the NOTCH1 pathway was overexpressed and activated. Strikingly, we confirmed this elevated expression level in leukemia patients. We also demonstrated that CAD204520 treatment of MLL r cells significantly reduces NOTCH1 and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule. Accordingly, treatment with CAD204520 resulted in dose-dependent reduced proliferation and viability, increased apoptosis, and the induction of cell cycle arrest via the downregulation of MLL and NOTCH1 target genes. In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in MLL r leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings.
- Published
- 2023
- Full Text
- View/download PDF
36. Modern treatment approaches to adult acute T-lymphoblastic and myeloid/T-lymphoblastic leukemia: from current standards to precision medicine.
- Author
-
Leoncin M, La Starza R, Roti G, Pagliaro L, Bassan R, and Mecucci C
- Subjects
- Adolescent, Humans, Neoplasm, Residual, Precision Medicine, Remission Induction, Young Adult, Hematopoietic Stem Cell Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
Purpose of Review: To review the most recent advancements in the management of adult T-cell acute lymphoblastic leukemia (T-ALL), we summarize insights into molecular diagnostics, immunotherapy, targeted therapy and new techniques of drug sensitivity profiling that may support further therapeutic progress in T-ALL subsets., Recent Findings: With current induction/consolidation chemotherapy and/or risk-oriented allogeneic stem cell transplantation programs up to 95% adult T-ALL patients achieve a remission and >50% (up to 80% in adolescents and young adults) are cured. The group of patients who fail upfront therapy, between 25% and 40%, is enriched in high-risk characteristics (unfavorable genetics, persistent minimal residual disease) and represents the ideal setting for the study of molecular mechanisms of disease resistance, and consequently explore novel ways of restoration of drug sensitivity and assess patient/subset-specific patterns of drug vulnerability to targeting agents, immunotherapy and cell therapy., Summary: The emerging evidence supports the contention that precision medicine may soon allow valuable therapeutic chances to adult patients with high-risk T-ALL. The ongoing challenge is to identify the best way to integrate all these new data into the therapeutic path of newly diagnosed patients, with a view to optimize the individual treatment plan and increase the cure rate., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
37. Β-blockers activate autophagy on infantile hemangioma-derived endothelial cells in vitro.
- Author
-
Lorusso B, Cerasoli G, Falco A, Frati C, Graiani G, Madeddu D, Nogara A, Corradini E, Roti G, Cerretani E, Gherli A, Caputi M, Gnetti L, Pilato FP, Quaini F, and Lagrasta C
- Subjects
- Adrenergic beta-Antagonists pharmacology, Amines, Atenolol pharmacology, Atenolol therapeutic use, Autophagy, Cell Proliferation, Child, Endothelial Cells, Humans, Macrolides, Metoprolol therapeutic use, Sirolimus pharmacology, Hemangioma pathology, Propranolol pharmacology, Propranolol therapeutic use
- Abstract
The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether β-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro., Material and Methods: Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy., Results: Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs., Conclusion: Our data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
38. Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol.
- Author
-
Messina M, Piciocchi A, Ottone T, Paolini S, Papayannidis C, Lessi F, Fracchiolla NS, Forghieri F, Candoni A, Mengarelli A, Martelli MP, Venditti A, Carella AM, Albano F, Mancini V, Massimo B, Arena V, Sargentini V, Sciumè M, Pastore D, Todisco E, Roti G, Siragusa S, Ladetto M, Pravato S, De Bellis E, Simonetti G, Marconi G, Cerchione C, Fazi P, Vignetti M, Amadori S, Martinelli G, and Voso MT
- Abstract
IDH1/2 mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of IDH1/2 mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19−86). Of these, 38 (14%) harbored IDH1 and 51 (18%) IDH2 mutations. IDH1/2 mutations were significantly associated with WHO PS >2 (p < 0.001) and non-complex karyotype (p = 0.021) when compared to IDH1/2-WT. Furthermore, patients with IDH1 mutations were more frequently NPM1-mutated (p = 0.007) and had a higher platelet count (p = 0.036). At relapse, IDH1/2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of IDH1/2-mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to IDH1/2-WT. In IDH1/2-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that IDH1/2 mutations are frequently detected at diagnosis and underlines the importance of recognizing IDH1/2-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors.
- Published
- 2022
- Full Text
- View/download PDF
39. Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia.
- Author
-
Montanaro A, Kitara S, Cerretani E, Marchesini M, Rompietti C, Pagliaro L, Gherli A, Su A, Minchillo ML, Caputi M, Fioretzaki R, Lorusso B, Ross L, Alexe G, Masselli E, Marozzi M, Rizzi FMA, La Starza R, Mecucci C, Xiong Y, Jin J, Falco A, Knoechel B, Aversa F, Candini O, Quaini F, Sportoletti P, Stegmaier K, and Roti G
- Subjects
- DNA Methylation genetics, Glycogen Synthase Kinase 3 metabolism, Histocompatibility Antigens metabolism, Humans, Nuclear Proteins metabolism, T-Lymphocytes metabolism, Histone-Lysine N-Methyltransferase metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Genomic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in acute lymphoblastic leukemia (ALL), suggesting new opportunities for therapeutic interventions. In this study, we identified G9a/EHMT2 as a potential target in T-ALL through the intersection of epigenome-centered shRNA and chemical screens. We subsequently validated G9a with low-throughput CRISPR-Cas9-based studies targeting the catalytic G9a SET-domain and the testing of G9a chemical inhibitors in vitro, 3D, and in vivo T-ALL models. Mechanistically we determined that G9a repression promotes lysosomal biogenesis and autophagic degradation associated with the suppression of sestrin2 (SESN2) and inhibition of glycogen synthase kinase-3 (GSK-3), suggesting that in T-ALL glycolytic dependent pathways are at least in part under epigenetic control. Thus, targeting G9a represents a strategy to exhaust the metabolic requirement of T-ALL cells., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
40. Validation of a radiomic approach to decipher NSCLC immune microenvironment in surgically resected patients.
- Author
-
Trentini F, Mazzaschi G, Milanese G, Pavone C, Madeddu D, Gnetti L, Frati C, Lorusso B, Lagrasta CAM, Minari R, Ampollini L, Ledda RE, Silva M, Sverzellati N, Quaini F, Roti G, and Tiseo M
- Subjects
- Aged, Carcinoma, Non-Small-Cell Lung diagnostic imaging, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Disease-Free Survival, Female, Humans, Lung diagnostic imaging, Lung metabolism, Lung pathology, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Male, Neoplasm Staging, Prognosis, Tomography, X-Ray Computed, Tumor Microenvironment immunology, B7-H1 Antigen genetics, CD8 Antigens genetics, Carcinoma, Non-Small-Cell Lung genetics, Tumor Microenvironment genetics
- Abstract
Radiomics has emerged as a noninvasive tool endowed with the potential to intercept tumor characteristics thereby predicting clinical outcome. In a recent study on resected non-small cell lung cancer (NSCLC), we identified highly prognostic computed tomography (CT) -derived radiomic features (RFs), which in turn were able to discriminate hot from cold tumor immune microenvironment (TIME). We aimed at validating a radiomic model capable of dissecting specific TIME profiles bearing prognostic power in resected NSCLC. The validation cohort included 31 radically resected NSCLCs clinicopathologically matched with the training set (n = 69). TIME was classified in hot and cold according to a multiparametric immunohistochemical analysis involving PD-L1 score and incidence of immune effector phenotypes among tumor infiltrating lymphocytes (TILs). High- throughput radiomic features (n = 841) extracted from CT images were correlated to TIME parameters to ultimately define prognostic classes. We confirmed PD-1 to CD8 ratio as best predictor of clinical outcome among TIME characteristics. Significantly prolonged overall survival (OS) was observed in patients carrying hot (median OS not reached) vs cold (median OS 22 months; hazard ratio 0.28, 95% confidence interval 0.09 -0.82; p = 0.015) immune background, thus validating the prognostic impact of these two TIME categories in resected NSCLC. Importantly, in the validation setting, three out of eight previously identified RFs sharply distinguishing hot from cold TIME were endorsed. Among signature-related RFs, Wavelet-HHH_gldm_HighGrayLevelEmphasis highly performed as descriptor of hot immune contexture (area under the receiver operating characteristic curve 0.94, 95% confidence interval 0.81 -1.00; p = 0.01). Based on our findings, Radiomics may decipher specific TIME profiles providing a noninvasive prognostic approach in resected NSCLC and an exploitable predictive strategy in advanced cases.
- Published
- 2022
- Full Text
- View/download PDF
41. Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.
- Author
-
Pikman Y, Ocasio-Martinez N, Alexe G, Dimitrov B, Kitara S, Diehl FF, Robichaud AL, Conway AS, Ross L, Su A, Ling F, Qi J, Roti G, Lewis CA, Puissant A, Vander Heiden MG, and Stegmaier K
- Subjects
- Animals, Antimetabolites, Antineoplastic pharmacology, Apoptosis, Cell Cycle, Cell Proliferation, Female, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma enzymology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, CRISPR-Cas Systems, Drug Resistance, Neoplasm drug effects, Enzyme Inhibitors pharmacology, Folic Acid metabolism, Glycine Hydroxymethyltransferase antagonists & inhibitors, Methotrexate pharmacology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
42. Lenvatinib Targets PDGFR-β Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights.
- Author
-
Iesato A, Li S, Roti G, Hacker MR, Fischer AH, and Nucera C
- Subjects
- Humans, Mutation, Pericytes metabolism, Pericytes pathology, Prognosis, Proto-Oncogene Proteins B-raf genetics, Thyroid Cancer, Papillary genetics, Thyroid Cancer, Papillary metabolism, Thyroid Cancer, Papillary pathology, Thyroid Neoplasms genetics, Thyroid Neoplasms metabolism, Thyroid Neoplasms pathology, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic drug effects, Pericytes drug effects, Phenylurea Compounds pharmacology, Quinolines pharmacology, Receptor, Platelet-Derived Growth Factor beta antagonists & inhibitors, Thyroid Cancer, Papillary drug therapy, Thyroid Neoplasms drug therapy
- Abstract
Context: Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-β [PDGFR-β]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also targets PDGFR-β. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression., Objectives: Develop a gene signature of pericyte abundance to assess with tumor aggressiveness and determine both the response of thyroid-derived pericytes to lenvatinib and their synergies with thyroid carcinoma-derived cells., Design: Using a new gene signature, we estimated the relative abundance of pericytes in papillary thyroid carcinoma (PTC) and normal thyroid (NT) TCGA samples. We also cocultured CD90+;PAX8- thyroid-derived pericytes and BRAFWT/V600E-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response., Results: Pericyte abundance is significantly higher in BRAFV600E-PTC with hTERT mutations and copy number alterations compared with NT or BRAFWT-PTC samples, even when data are corrected for clinical-pathologic confounders. We have identified upregulated pathways important for tumor survival, immunomodulation, RNA transcription, cell-cycle regulation, and cholesterol metabolism. Pericyte growth is significantly increased by platelet-derived growth factor-BB, which activates phospho(p)-PDGFR-β, pERK1/2, and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT, and p-p70S6-kinase downstream PDGFR-β. Critically, lenvatinib significantly induces higher BRAFWT/V600E-PTC cell death when cocultured with pericytes, as a result of pericyte targeting via PDGFR-β., Conclusions: This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
43. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia.
- Author
-
Di Giacomo D, La Starza R, Gorello P, Pellanera F, Kalender Atak Z, De Keersmaecker K, Pierini V, Harrison CJ, Arniani S, Moretti M, Testoni N, De Santis G, Roti G, Matteucci C, Bassan R, Vandenberghe P, Aerts S, Cools J, Bornhauser B, Bourquin JP, Piazza R, and Mecucci C
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Biomarkers, Tumor biosynthesis, Biomarkers, Tumor genetics, Chromosomes, Human, Pair 14 genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Repressor Proteins biosynthesis, Repressor Proteins genetics, Translocation, Genetic, Tumor Suppressor Proteins biosynthesis, Tumor Suppressor Proteins genetics
- Abstract
Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
- View/download PDF
44. An Introduction to the Study of Medieval Latin Versification
- Author
-
Norberg, Dag, Roti, Grant C., de La Chapelle Skubly, Jacqueline, Ziolkowski, Jan, edited with an introduction by, Norberg, Dag, Roti, Grant C., de La Chapelle Skubly, Jacqueline, and Ziolkowski, Jan
- Published
- 2012
- Full Text
- View/download PDF
45. MYB rearrangements and over-expression in T-cell acute lymphoblastic leukemia.
- Author
-
Bardelli V, Arniani S, Pierini V, Pierini T, Di Giacomo D, Gorello P, Moretti M, Pellanera F, Elia L, Vitale A, Storlazzi CT, Tolomeo D, Mastrodicasa E, Caniglia M, Chiaretti S, Ruggeri L, Roti G, Schwab C, Harrison CJ, Almeida A, Pieters T, Van Vlierberghe P, Mecucci C, and La Starza R
- Subjects
- Adolescent, Biomarkers, Tumor metabolism, Child, Child, Preschool, Down-Regulation, F-Box-WD Repeat-Containing Protein 7 genetics, Female, Homeobox Protein Nkx-2.2 genetics, Homeodomain Proteins genetics, Humans, Infant, Male, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Proto-Oncogene Proteins c-myb metabolism, Receptor, Notch1 genetics, Thyroid Nuclear Factor 1 genetics, Biomarkers, Tumor genetics, Gene Duplication, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins c-myb genetics
- Abstract
We investigated MYB rearrangements (MYB-R) and the levels of MYB expression, in 331 pediatric and adult patients with T-cell acute lymphoblastic leukemia (T-ALL). MYB-R were detected in 17 cases and consisted of MYB tandem duplication (tdup) (= 14) or T cell receptor beta locus (TRB)-MYB (= 3). As previously reported, TRB-MYB was found only in children (1.6%) while MYB tdup occurred in both age groups, although it was slightly more frequent in children (5.2% vs 2.8%). Shared features of MYB-R T-ALL were a non-early T-cell precursor (ETP) phenotype, a high incidence of NOTCH1/FBXW7 mutations (81%) and CDKN2AB deletions (70.5%). Moreover, they mainly belonged to HOXA (=8), NKX2-1/2-2/TLX1 (=4), and TLX3 (=3) homeobox-related subgroups. Overall, MYB-R cases had significantly higher levels of MYB expression than MYB wild type (MYB-wt) cases, although high levels of MYB were detected in ~ 30% of MYB-wt T-ALL. Consistent with the transcriptional regulatory networks, cases with high MYB expression were significantly enriched within the TAL/LMO subgroup (P = .017). Interestingly, analysis of paired diagnosis/remission samples demonstrated that a high MYB expression was restricted to the leukemic clone. Our study has indicated that different mechanisms underlie MYB deregulation in 30%-40% of T-ALL and highlighted that, MYB has potential as predictive/prognostic marker and/or target for tailored therapy., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
46. Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis.
- Author
-
Masselli E, Carubbi C, Pozzi G, Percesepe A, Campanelli R, Villani L, Gobbi G, Bonomini S, Roti G, Rosti V, Massa M, Barosi G, and Vitale M
- Abstract
Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2-one of the most potent immunomodulatory chemokines-to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.
- Published
- 2021
- Full Text
- View/download PDF
47. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.
- Author
-
Gocho Y, Liu J, Hu J, Yang W, Dharia NV, Zhang J, Shi H, Du G, John A, Lin TN, Hunt J, Huang X, Ju B, Rowland L, Shi L, Maxwell D, Smart B, Crews KR, Yang W, Hagiwara K, Zhang Y, Roberts K, Wang H, Jabbour E, Stock W, Eisfelder B, Paietta E, Newman S, Roti G, Litzow M, Easton J, Zhang J, Peng J, Chi H, Pounds S, Relling MV, Inaba H, Zhu X, Kornblau S, Pui CH, Konopleva M, Teachey D, Mullighan CG, Stegmaier K, Evans WE, Yu J, and Yang JJ
- Subjects
- Cell Line, Tumor, Dasatinib pharmacology, Humans, Network Pharmacology, Proto-Oncogene Proteins c-bcl-2 genetics, T-Lymphocytes, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities ex vivo , we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
- Published
- 2021
- Full Text
- View/download PDF
48. Targeting oncogenic Notch signaling with SERCA inhibitors.
- Author
-
Pagliaro L, Marchesini M, and Roti G
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Molecular Targeted Therapy, Neoplasms metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Receptors, Notch metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Thapsigargin analogs & derivatives, Thapsigargin pharmacology, Thapsigargin therapeutic use, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Neoplasms drug therapy, Receptors, Notch antagonists & inhibitors, Sarcoplasmic Reticulum Calcium-Transporting ATPases antagonists & inhibitors, Signal Transduction drug effects
- Abstract
P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacology. Clinical transition has been safely achieved for H
+ /K+ ATPase inhibitors such as omeprazole and Na+ /K+ -ATPase inhibitors like digoxin. However, this is more challenging for Ca2+ -ATPase modulators due to the physiological role of Ca2+ in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca2+ -ATPase (SERCA) modulators have been studied as potential chemotherapy agents because of their Ca2+ -mediated pan-cancer lethal effects. Instead, recent evidence suggests that SERCA inhibition suppresses oncogenic Notch1 signaling emerging as an alternative to γ-secretase modulators that showed limited clinical activity due to severe side effects. In this review, we focus on how SERCA inhibitors alter Notch1 signaling and show that Notch on-target-mediated antileukemia properties of these molecules can be achieved without causing overt Ca2+ cellular overload.- Published
- 2021
- Full Text
- View/download PDF
49. Activating somatic and germline TERT promoter variants in myeloid malignancies.
- Author
-
Nofrini V, Matteucci C, Pellanera F, Gorello P, Di Giacomo D, Lema Fernandez AG, Nardelli C, Iannotti T, Brandimarte L, Arniani S, Moretti M, Gili A, Roti G, Di Battista V, Colla S, and Mecucci C
- Subjects
- Alleles, Genotype, Humans, Leukemia, Myeloid diagnosis, Genetic Association Studies methods, Genetic Predisposition to Disease, Germ-Line Mutation, Leukemia, Myeloid genetics, Mutation, Promoter Regions, Genetic, Telomerase genetics
- Published
- 2021
- Full Text
- View/download PDF
50. The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.
- Author
-
Su A, Ling F, Vaganay C, Sodaro G, Benaksas C, Dal Bello R, Forget A, Pardieu B, Lin KH, Rutter JC, Bassil CF, Fortin G, Pasanisi J, Antony-Debré I, Alexe G, Benoist JF, Pruvost A, Pikman Y, Qi J, Schlageter MH, Micol JB, Roti G, Cluzeau T, Dombret H, Preudhomme C, Fenouille N, Benajiba L, Golan HM, Stegmaier K, Lobry C, Wood KC, Itzykson R, and Puissant A
- Subjects
- Animals, Clustered Regularly Interspaced Short Palindromic Repeats, Drug Resistance, Neoplasm, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Molecular Targeted Therapy, Proto-Oncogene Proteins c-myc biosynthesis, U937 Cells, Folic Acid metabolism, Methylenetetrahydrofolate Reductase (NADPH2) metabolism, Neoplasms drug therapy, Neoplasms metabolism
- Abstract
Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH
3 -THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies. SIGNIFICANCE: Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3 -THF supplementation thus represents a low-risk intervention to enhance their effects. See related commentary by Marando and Huntly, p. 1791 . This article is highlighted in the In This Issue feature, p. 1775 ., (©2020 American Association for Cancer Research.)- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.