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535 results on '"Stevenson, Kristen E."'

1. Molecular map of chronic lymphocytic leukemia and its impact on outcome

Author

Knisbacher, Binyamin A, Lin, Ziao, Hahn, Cynthia K, Nadeu, Ferran, Duran-Ferrer, Martí, Stevenson, Kristen E, Tausch, Eugen, Delgado, Julio, Barbera-Mourelle, Alex, Taylor-Weiner, Amaro, Bousquets-Muñoz, Pablo, Diaz-Navarro, Ander, Dunford, Andrew, Anand, Shankara, Kretzmer, Helene, Gutierrez-Abril, Jesus, López-Tamargo, Sara, Fernandes, Stacey M, Sun, Clare, Sivina, Mariela, Rassenti, Laura Z, Schneider, Christof, Li, Shuqiang, Parida, Laxmi, Meissner, Alexander, Aguet, François, Burger, Jan A, Wiestner, Adrian, Kipps, Thomas J, Brown, Jennifer R, Hallek, Michael, Stewart, Chip, Neuberg, Donna S, Martín-Subero, José I, Puente, Xose S, Stilgenbauer, Stephan, Wu, Catherine J, Campo, Elias, and Getz, Gad

Subjects
Hematology, Clinical Research, Cancer, Human Genome, Rare Diseases, Biotechnology, Genetics, Lymphoma, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Immunoglobulin Variable Region, Mutation, Prognosis, Genomics, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

Published
2022

2. Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia

Author

Lane, Andrew A., Garcia, Jacqueline S., Raulston, Evangeline G., Garzon, Jada L., Galinsky, Ilene, Baxter, Emilie W., Leonard, Rebecca, DeAngelo, Daniel J., Luskin, Marlise R., Reilly, Christopher R., Stahl, Maximilian, Stone, Richard M., Vedula, Rahul S., Wadleigh, Martha M., Winer, Eric S., Mughal, Tariq, Brooks, Christopher, Gupta, Ira V., Stevenson, Kristen E., Neuberg, Donna S., Ren, Siyang, Keating, Julia, Konopleva, Marina, Stein, Anthony, and Pemmaraju, Naveen

Published
2024
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3. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Author

Bernard, Elsa, Nannya, Yasuhito, Hasserjian, Robert P, Devlin, Sean M, Tuechler, Heinz, Medina-Martinez, Juan S, Yoshizato, Tetsuichi, Shiozawa, Yusuke, Saiki, Ryunosuke, Malcovati, Luca, Levine, Max F, Arango, Juan E, Zhou, Yangyu, Solé, Francesc, Cargo, Catherine A, Haase, Detlef, Creignou, Maria, Germing, Ulrich, Zhang, Yanming, Gundem, Gunes, Sarian, Araxe, van de Loosdrecht, Arjan A, Jädersten, Martin, Tobiasson, Magnus, Kosmider, Olivier, Follo, Matilde Y, Thol, Felicitas, Pinheiro, Ronald F, Santini, Valeria, Kotsianidis, Ioannis, Boultwood, Jacqueline, Santos, Fabio PS, Schanz, Julie, Kasahara, Senji, Ishikawa, Takayuki, Tsurumi, Hisashi, Takaori-Kondo, Akifumi, Kiguchi, Toru, Polprasert, Chantana, Bennett, John M, Klimek, Virginia M, Savona, Michael R, Belickova, Monika, Ganster, Christina, Palomo, Laura, Sanz, Guillermo, Ades, Lionel, Della Porta, Matteo Giovanni, Elias, Harold K, Smith, Alexandra G, Werner, Yesenia, Patel, Minal, Viale, Agnès, Vanness, Katelynd, Neuberg, Donna S, Stevenson, Kristen E, Menghrajani, Kamal, Bolton, Kelly L, Fenaux, Pierre, Pellagatti, Andrea, Platzbecker, Uwe, Heuser, Michael, Valent, Peter, Chiba, Shigeru, Miyazaki, Yasushi, Finelli, Carlo, Voso, Maria Teresa, Shih, Lee-Yung, Fontenay, Michaela, Jansen, Joop H, Cervera, José, Atsuta, Yoshiko, Gattermann, Norbert, Ebert, Benjamin L, Bejar, Rafael, Greenberg, Peter L, Cazzola, Mario, Hellström-Lindberg, Eva, Ogawa, Seishi, and Papaemmanuil, Elli

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Hematology, Stem Cell Research, Cancer, Clinical Research, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Alleles, Cohort Studies, DNA Copy Number Variations, DNA Mutational Analysis, Female, Gene Frequency, Genomic Instability, Humans, Loss of Heterozygosity, Male, Mutation, Myelodysplastic Syndromes, Phenotype, Prognosis, Survival Analysis, Treatment Outcome, Tumor Suppressor Protein p53, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6-8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.

Published
2020

5. New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

Author

Arwood, Matthew L., Liu, Yao, Harkins, Shannon K., Weinstock, David M., Yang, Lei, Stevenson, Kristen E., Plana, Olivia D., Dong, Jingyun, Cirka, Haley, Jones, Kristen L., Virtanen, Anniina T., Gupta, Dikshat G., Ceas, Amanda, Lawney, Brian, Yoda, Akinori, Leahy, Catharine, Hao, Mingfeng, He, Zhixiang, Choi, Hwan Geun, Wang, Yaning, Silvennoinen, Olli, Hubbard, Stevan R., Zhang, Tinghu, Gray, Nathanael S., and Li, Loretta S.

Published
2023
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7. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups.

Author

Haase, Detlef, Stevenson, Kristen E, Neuberg, Donna, Maciejewski, Jaroslaw P, Nazha, Aziz, Sekeres, Mikkael A, Ebert, Benjamin L, Garcia-Manero, Guillermo, Haferlach, Claudia, Haferlach, Torsten, Kern, Wolfgang, Ogawa, Seishi, Nagata, Yasunobu, Yoshida, Kenichi, Graubert, Timothy A, Walter, Matthew J, List, Alan F, Komrokji, Rami S, Padron, Eric, Sallman, David, Papaemmanuil, Elli, Campbell, Peter J, Savona, Michael R, Seegmiller, Adam, Adès, Lionel, Fenaux, Pierre, Shih, Lee-Yung, Bowen, David, Groves, Michael J, Tauro, Sudhir, Fontenay, Michaela, Kosmider, Olivier, Bar-Natan, Michal, Steensma, David, Stone, Richard, Heuser, Michael, Thol, Felicitas, Cazzola, Mario, Malcovati, Luca, Karsan, Aly, Ganster, Christina, Hellström-Lindberg, Eva, Boultwood, Jacqueline, Pellagatti, Andrea, Santini, Valeria, Quek, Lynn, Vyas, Paresh, Tüchler, Heinz, Greenberg, Peter L, Bejar, Rafael, and International Working Group for MDS Molecular Prognostic Committee

Subjects
International Working Group for MDS Molecular Prognostic Committee, Humans, Myelodysplastic Syndromes, Chromosome Aberrations, Prognosis, Combined Modality Therapy, Survival Rate, Follow-Up Studies, Karyotyping, Mutation, Aged, Aged, 80 and over, Middle Aged, Female, Male, Tumor Suppressor Protein p53, Biomarkers, Tumor, Hematology, Rare Diseases, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Immunology
Abstract

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p 10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

Published
2019

9. Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1

Author

Wu, Wenchao, Nelson, Geoffrey M., Koch, Raphael, Donovan, Katherine A., Nowak, Radosław P., Heavican-Foral, Tayla B., Nirmal, Ajit J., Liu, Huiyun, Yang, Lei, Duffy, Jessica, Powers, Foster, Stevenson, Kristen E., Jones, Marcus Kenneth, Ng, Samuel Y., Wu, Gongwei, Jain, Salvia, Xu, Ran, Amaka, Sam, Trevisani, Christopher, Donaldson, Nicholas L., Hagner, Patrick R., de Leval, Laurence, Gaulard, Philippe, Iqbal, Javeed, Thakurta, Anjan, Fischer, Eric S., Adelman, Karen, and Weinstock, David M.

Published
2022
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10. Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001

Author

Tran, Thai Hoa, Langlois, Sylvie, Meloche, Caroline, Caron, Maxime, Saint-Onge, Pascal, Rouette, Alexandre, Bataille, Alain R., Jimenez-Cortes, Camille, Sontag, Thomas, Bittencourt, Henrique, Laverdière, Caroline, Lavallée, Vincent-Philippe, Leclerc, Jean-Marie, Cole, Peter D., Gennarini, Lisa M., Kahn, Justine M., Kelly, Kara M., Michon, Bruno, Santiago, Raoul, Stevenson, Kristen E., Welch, Jennifer J.G., Schroeder, Kaitlin M., Koch, Victoria, Cellot, Sonia, Silverman, Lewis B., and Sinnett, Daniel

Published
2022
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11. Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia

Author

Pouliot, Gayle P, Degar, James, Hinze, Laura, Kochupurakkal, Bose, Vo, Chau D, Burns, Melissa A, Moreau, Lisa, Ganesa, Chirag, Roderick, Justine, Peirs, Sofie, Menten, Bjorn, Loh, Mignon L, Hunger, Stephen P, Silverman, Lewis B, Harris, Marian H, Stevenson, Kristen E, Weinstock, David M, Weng, Andrew P, Van Vlierberghe, Pieter, D’Andrea, Alan D, and Gutierrez, Alejandro

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Hematology, Pediatric Cancer, Orphan Drug, Pediatric, Childhood Leukemia, Pediatric Research Initiative, Cancer, Rare Diseases, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Animals, BRCA2 Protein, Cell Line, Tumor, Child, Fanconi Anemia Complementation Group D2 Protein, Genes, BRCA1, Genes, BRCA2, Haploinsufficiency, Heterografts, Humans, Jurkat Cells, Male, Mice, Mice, Inbred NOD, Mutagenesis, Site-Directed, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Radiation Tolerance, Sequence Analysis, DNA, Sequence Analysis, RNA, Ultraviolet Rays, General Science & Technology
Abstract

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.

Published
2019

12. PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

Author

Ariës, Ingrid M, Bodaar, Kimberly, Karim, Salmaan A, Chonghaile, Triona Ni, Hinze, Laura, Burns, Melissa A, Pfirrmann, Maren, Degar, James, Landrigan, Jack T, Balbach, Sebastian, Peirs, Sofie, Menten, Björn, Isenhart, Randi, Stevenson, Kristen E, Neuberg, Donna S, Devidas, Meenakshi, Loh, Mignon L, Hunger, Stephen P, Teachey, David T, Rabin, Karen R, Winter, Stuart S, Dunsmore, Kimberly P, Wood, Brent L, Silverman, Lewis B, Sallan, Stephen E, Van Vlierberghe, Pieter, Orkin, Stuart H, Knoechel, Birgit, Letai, Anthony G, and Gutierrez, Alejandro

Subjects
Childhood Leukemia, Hematology, Genetics, Cancer, Stem Cell Research, Pediatric, Rare Diseases, Pediatric Cancer, Development of treatments and therapeutic interventions, 1.1 Normal biological development and functioning, Underpinning research, 5.1 Pharmaceuticals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Leukemic, Humans, Male, Mitochondria, Neoplasm Proteins, Polycomb Repressive Complex 2, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Transcription, Genetic, Up-Regulation, Medical and Health Sciences, Immunology
Abstract

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1 These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.

Published
2018

13. Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia

Author

Burns, Melissa A, Liao, Zi Wei, Yamagata, Natsuko, Pouliot, Gayle P, Stevenson, Kristen E, Neuberg, Donna S, Thorner, Aaron R, Ducar, Matthew, Silverman, Emily A, Hunger, Stephen P, Loh, Mignon L, Winter, Stuart S, Dunsmore, Kimberly P, Wood, Brent, Devidas, Meenakshi, Harris, Marian H, Silverman, Lewis B, Sallan, Stephen E, and Gutierrez, Alejandro

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Cancer, Pediatric, Rare Diseases, Hematology, Pediatric Cancer, Childhood Leukemia, Genetics, 2.1 Biological and endogenous factors, Adolescent, Animals, Carcinogenesis, Cell Transformation, Neoplastic, Child, Child, Preschool, Female, Hedgehog Proteins, Humans, Male, Mutation, Oncogenes, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Signal Transduction, T-Lymphocytes, Zebrafish, Clinical Sciences, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.

Published
2018

15. Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease

Author

Winter, Peter S., primary, Ramseier, Michelle L., additional, Navia, Andrew W., additional, Saksena, Sachit, additional, Strouf, Haley, additional, Senhaji, Nezha, additional, DenAdel, Alan, additional, Mirza, Mahnoor, additional, An, Hyun Hwan, additional, Bilal, Laura, additional, Dennis, Peter, additional, Leahy, Catharine S., additional, Shigemori, Kay, additional, Galvez-Reyes, Jennyfer, additional, Zhang, Ye, additional, Powers, Foster, additional, Mulugeta, Nolawit, additional, Gupta, Alejandro J., additional, Calistri, Nicholas, additional, Van Scoyk, Alex, additional, Jones, Kristen, additional, Liu, Huiyun, additional, Stevenson, Kristen E., additional, Ren, Siyang, additional, Luskin, Marlise R., additional, Couturier, Charles P., additional, Amini, Ava P., additional, Raghavan, Srivatsan, additional, Kimmerling, Robert J., additional, Stevens, Mark M., additional, Crawford, Lorin, additional, Weinstock, David M., additional, Manalis, Scott R., additional, Shalek, Alex K., additional, and Murakami, Mark A., additional

Published
2024
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18. Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features

Author

Zhou, Xiaolong Alan, Yang, Jingyi, Ringbloom, Kimberly G., Martinez-Escala, Maria Estela, Stevenson, Kristen E., Wenzel, Alexander T., Fantini, Damiano, Martin, Haley K., Moy, Andrea P., Morgan, Elizabeth A., Harkins, Shannon, Paxton, Christian N., Hong, Bo, Andersen, Erica F., Guitart, Joan, Weinstock, David M., Cerroni, Lorenzo, Choi, Jaehyuk, and Louissaint, Abner, Jr

Published
2021
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19. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

Author

Townsend, Elizabeth C, Murakami, Mark A, Christodoulou, Alexandra, Christie, Amanda L, Köster, Johannes, DeSouza, Tiffany A, Morgan, Elizabeth A, Kallgren, Scott P, Liu, Huiyun, Wu, Shuo-Chieh, Plana, Olivia, Montero, Joan, Stevenson, Kristen E, Rao, Prakash, Vadhi, Raga, Andreeff, Michael, Armand, Philippe, Ballen, Karen K, Barzaghi-Rinaudo, Patrizia, Cahill, Sarah, Clark, Rachael A, Cooke, Vesselina G, Davids, Matthew S, DeAngelo, Daniel J, Dorfman, David M, Eaton, Hilary, Ebert, Benjamin L, Etchin, Julia, Firestone, Brant, Fisher, David C, Freedman, Arnold S, Galinsky, Ilene A, Gao, Hui, Garcia, Jacqueline S, Garnache-Ottou, Francine, Graubert, Timothy A, Gutierrez, Alejandro, Halilovic, Ensar, Harris, Marian H, Herbert, Zachary T, Horwitz, Steven M, Inghirami, Giorgio, Intlekofer, Andrew M, Ito, Moriko, Izraeli, Shai, Jacobsen, Eric D, Jacobson, Caron A, Jeay, Sébastien, Jeremias, Irmela, Kelliher, Michelle A, Koch, Raphael, Konopleva, Marina, Kopp, Nadja, Kornblau, Steven M, Kung, Andrew L, Kupper, Thomas S, LeBoeuf, Nicole R, LaCasce, Ann S, Lees, Emma, Li, Loretta S, Look, A Thomas, Murakami, Masato, Muschen, Markus, Neuberg, Donna, Ng, Samuel Y, Odejide, Oreofe O, Orkin, Stuart H, Paquette, Rachel R, Place, Andrew E, Roderick, Justine E, Ryan, Jeremy A, Sallan, Stephen E, Shoji, Brent, Silverman, Lewis B, Soiffer, Robert J, Steensma, David P, Stegmaier, Kimberly, Stone, Richard M, Tamburini, Jerome, Thorner, Aaron R, van Hummelen, Paul, Wadleigh, Martha, Wiesmann, Marion, Weng, Andrew P, Wuerthner, Jens U, Williams, David A, Wollison, Bruce M, Lane, Andrew A, Letai, Anthony, Bertagnolli, Monica M, Ritz, Jerome, Brown, Myles, Long, Henry, Aster, Jon C, Shipp, Margaret A, Griffin, James D, and Weinstock, David M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Clinical Trials and Supportive Activities, Orphan Drug, Clinical Research, Hematology, Cancer, Rare Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Good Health and Well Being, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Lineage, Female, Gene Expression Profiling, Genes, p53, Heterografts, Humans, Internet, Isoquinolines, Leukemia, Leukemia, Experimental, Lymphoma, Male, Mice, Mice, Inbred NOD, Molecular Targeted Therapy, Neoplasm Proteins, Neoplasm Transplantation, Phenotype, Piperazines, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proteome, Proto-Oncogene Proteins c-mdm2, Random Allocation, Randomized Controlled Trials as Topic, Research Design, Tissue Banks, Transcriptome, Xenograft Model Antitumor Assays, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.

Published
2016

21. Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia

Author

Lane, Andrew A., primary, Garcia, Jacqueline S, additional, Raulston, Evangeline G., additional, Garzon, Jada Lauren N., additional, Galinsky, Ilene, additional, Baxter, Emilie W., additional, Leonard, Rebecca, additional, DeAngelo, Daniel J, additional, Luskin, Marlise R, additional, Reilly, Christopher R., additional, Stahl, Maximilian, additional, Stone, Richard M, additional, Vedula, Rahul S., additional, Wadleigh, Martha, additional, Winer, Eric S, additional, Mughal, Tariq I, additional, Brooks, Christopher, additional, Gupta, Ira V., additional, Stevenson, Kristen E., additional, Neuberg, Donna S., additional, Ren, Siyang, additional, Keating, Julia H., additional, Konopleva, Marina Y., additional, Stein, Anthony S., additional, and Pemmaraju, Naveen, additional

Published
2023
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22. Parp3 promotes long-range end joining in murine cells

Author

Layer, Jacob V., Cleary, J. Patrick, Brown, Alexander J., Stevenson, Kristen E., Morrow, Sara N., Van Scoyk, Alexandria, Blasco, Rafael B., Karaca, Elif, Meng, Fei-Long, Frock, Richard L., Tivey, Trevor, Kim, Sunhee, Fuchs, Hailey, Chiarle, Roberto, Alt, Frederick W., Roberts, Steven A., Weinstock, David M., and Day, Tovah A.

Published
2018

23. Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001

Author

Vrooman, Lynda M., Blonquist, Traci M., Harris, Marian H., Stevenson, Kristen E., Place, Andrew E., Hunt, Sarah K., O'Brien, Jane E., Asselin, Barbara L., Athale, Uma H., Clavell, Luis A., Cole, Peter D., Kelly, Kara M., Laverdiere, Caroline, Leclerc, Jean-Marie, Michon, Bruno, Schorin, Marshall A., Sulis, Maria Luisa, Welch, Jennifer J.G., Neuberg, Donna S., Sallan, Stephen E., and Silverman, Lewis B.

Published
2018
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24. Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia

Author

Tran, Thai Hoa, Harris, Marian H., Nguyen, Jonathan V., Blonquist, Traci M., Stevenson, Kristen E., Stonerock, Eileen, Asselin, Barbara L., Athale, Uma H., Clavell, Luis A., Cole, Peter D., Kelly, Kara M., Laverdiere, Caroline, Leclerc, Jean-Marie, Michon, Bruno, Schorin, Marshall A., Welch, Jennifer J.G., Reshmi, Shalini C., Neuberg, Donna S., Sallan, Stephen E., Loh, Mignon L., and Silverman, Lewis B.

Published
2018
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25. TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence

Author

Wu, Gongwei, primary, Yoshida, Noriaki, additional, Liu, Jihe, additional, Zhang, Xiaoyang, additional, Xiong, Yuan, additional, Heavican-Foral, Tayla B., additional, Mandato, Elisa, additional, Liu, Huiyun, additional, Nelson, Geoffrey M., additional, Yang, Lu, additional, Chen, Renee, additional, Donovan, Katherine A., additional, Jones, Marcus K., additional, Roshal, Mikhail, additional, Zhang, Yanming, additional, Xu, Ran, additional, Nirmal, Ajit J., additional, Jain, Salvia, additional, Leahy, Catharine, additional, Jones, Kristen L., additional, Stevenson, Kristen E., additional, Galasso, Natasha, additional, Ganesan, Nivetha, additional, Chang, Tiffany, additional, Wu, Wen-Chao, additional, Louissaint, Abner, additional, Debaize, Lydie, additional, Yoon, Hojong, additional, Dal Cin, Paola, additional, Chan, Wing C., additional, Ho Sui, Shannan J., additional, Ng, Samuel Y., additional, Feldman, Andrew L., additional, Horwitz, Steven M., additional, Adelman, Karen, additional, Fischer, Eric S., additional, Chen, Chun-Wei, additional, Weinstock, David M., additional, and Brown, Myles, additional

Published
2023
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27. Impairment of health‐related quality of life for children with acute lymphoblastic leukemia over the first year of therapy: A report from the DFCI ALL Consortium

Author

Welch, Jennifer J. G., primary, Flamand, Yael, additional, Stevenson, Kristen E., additional, Neuberg, Donna S., additional, Athale, Uma H., additional, Kelly, Kara M., additional, Laverdiere, Caroline, additional, Michon, Bruno, additional, Place, Andrew E., additional, Sallan, Stephen E., additional, Silverman, Lewis B., additional, and Vrooman, Lynda M., additional

Published
2023
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28. Author Correction: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Author

Bernard, Elsa, Nannya, Yasuhito, Hasserjian, Robert P., Devlin, Sean M., Tuechler, Heinz, Medina-Martinez, Juan S., Yoshizato, Tetsuichi, Shiozawa, Yusuke, Saiki, Ryunosuke, Malcovati, Luca, Levine, Max F., Arango, Juan E., Zhou, Yangyu, Solé, Francesc, Cargo, Catherine A., Haase, Detlef, Creignou, Maria, Germing, Ulrich, Zhang, Yanming, Gundem, Gunes, Sarian, Araxe, van de Loosdrecht, Arjan A., Jädersten, Martin, Tobiasson, Magnus, Kosmider, Olivier, Follo, Matilde Y., Thol, Felicitas, Pinheiro, Ronald F., Santini, Valeria, Kotsianidis, Ioannis, Boultwood, Jacqueline, Santos, Fabio P. S., Schanz, Julie, Kasahara, Senji, Ishikawa, Takayuki, Tsurumi, Hisashi, Takaori-Kondo, Akifumi, Kiguchi, Toru, Polprasert, Chantana, Bennett, John M., Klimek, Virginia M., Savona, Michael R., Belickova, Monika, Ganster, Christina, Palomo, Laura, Sanz, Guillermo, Ades, Lionel, Della Porta, Matteo Giovanni, Elias, Harold K., Smith, Alexandra G., Werner, Yesenia, Patel, Minal, Viale, Agnès, Vanness, Katelynd, Neuberg, Donna S., Stevenson, Kristen E., Menghrajani, Kamal, Bolton, Kelly L., Fenaux, Pierre, Pellagatti, Andrea, Platzbecker, Uwe, Heuser, Michael, Valent, Peter, Chiba, Shigeru, Miyazaki, Yasushi, Finelli, Carlo, Voso, Maria Teresa, Shih, Lee-Yung, Fontenay, Michaela, Jansen, Joop H., Cervera, José, Atsuta, Yoshiko, Gattermann, Norbert, Ebert, Benjamin L., Bejar, Rafael, Greenberg, Peter L., Cazzola, Mario, Hellström-Lindberg, Eva, Ogawa, Seishi, and Papaemmanuil, Elli

Published
2021
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29. Supplementary Table 5 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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30. Supplementary Table 4 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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31. Supplementary Table 2 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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32. Data from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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33. Supplementary Table 6 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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34. Supplementary Table 3 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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35. Supplementary Table 7 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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36. Supplementary Table 1 from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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37. Supplementary Figures and Methods from Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Author

Lossos, Chen, primary, Liu, Yunpeng, primary, Kolb, Kellie E., primary, Christie, Amanda L., primary, Van Scoyk, Alexandria, primary, Prakadan, Sanjay M., primary, Shigemori, Kay, primary, Stevenson, Kristen E., primary, Morrow, Sara, primary, Plana, Olivia D., primary, Fraser, Cameron, primary, Jones, Kristen L., primary, Liu, Huiyun, primary, Pallasch, Christian P., primary, Modiste, Rebecca, primary, Nguyen, Quang-De, primary, Craig, Jeffrey W., primary, Morgan, Elizabeth A., primary, Vega, Francisco, primary, Aster, Jon C., primary, Sarosiek, Kristopher A., primary, Shalek, Alex K., primary, Hemann, Michael T., primary, and Weinstock, David M., primary

Published
2023
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38. Intravenous pegylated asparaginase versus intramuscular native Escherichia colil-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial

Author

Place, Andrew E, Stevenson, Kristen E, Vrooman, Lynda M, Harris, Marian H, Hunt, Sarah K, O'Brien, Jane E, Supko, Jeffrey G, Asselin, Barbara L, Athale, Uma H, Clavell, Luis A, Cole, Peter D, Kelly, Kara M, Laverdiere, Caroline, Leclerc, Jean-Marie, Michon, Bruno, Schorin, Marshall A, Welch, Jennifer J G, Lipshultz, Steven E, Kutok, Jeffery L, Blonquist, Traci M, Neuberg, Donna S, Sallan, Stephen E, and Silverman, Lewis B

Published
2015
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39. TP63 Fusions Drive Enhancer Rewiring, Lymphomagenesis, and Dependence on EZH2

Author

Wu, Gongwei, primary, Yoshida, Noriaki, additional, Liu, Jihe, additional, Zhang, Xiaoyang, additional, Heavican-Foral, Tayla B., additional, Liu, Huiyun, additional, Nelson, Geoffrey M., additional, Yang, Lu, additional, Chen, Renee, additional, Jones, Marcus Kenneth, additional, Xu, Ran, additional, Nirmal, Ajit Johnson, additional, Jain, Salvia, additional, Leahy, Catharine, additional, Jones, Kristen Lynn, additional, Stevenson, Kristen E., additional, Wu, Wenchao, additional, Louissaint, Abner, additional, Debaize, Lydie, additional, Chan, Wing C., additional, Ho Sui, Shannan, additional, Ng, Samuel, additional, Feldman, Andrew L., additional, Meyerson, Matthew, additional, Adelman, Karen, additional, Chen, chun-Wei David, additional, Brown, Myles, additional, and Weinstock, David M., additional

Published
2022
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40. Intensity of Induction Regimen and Outcomes Among Adults with Ph+ ALL Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Author

Raman, Hari S., primary, Kim, Se Eun, additional, DeAngelo, Daniel J, additional, Stevenson, Kristen E., additional, Neuberg, Donna S., additional, Winer, Eric S., additional, Wadleigh, Martha, additional, Garcia, Jacqueline S., additional, Kim, Annette S., additional, Stone, Richard M., additional, Ho, Vincent T, additional, and Luskin, Marlise R., additional

Published
2022
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41. Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Author

Wang, Lili, Shalek, Alex K., Lawrence, Mike, Ding, Ruihua, Gaublomme, Jellert T., Pochet, Nathalie, Stojanov, Petar, Sougnez, Carrie, Shukla, Sachet A., Stevenson, Kristen E., Zhang, Wandi, Wong, Jessica, Sievers, Quinlan L., MacDonald, Bryan T., Vartanov, Alexander R., Goldstein, Natalie R., Neuberg, Donna, He, Xi, Lander, Eric, Hacohen, Nir, Regev, Aviv, Getz, Gad, Brown, Jennifer R., Park, Hongkun, and Wu, Catherine J.

Published
2014
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42. Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Author

Ng, Samuel Y., Yoshida, Noriaki, Christie, Amanda L., Ghandi, Mahmoud, Dharia, Neekesh V., Dempster, Joshua, Murakami, Mark, Shigemori, Kay, Morrow, Sara N., Van Scoyk, Alexandria, Cordero, Nicolas A., Stevenson, Kristen E., Puligandla, Maneka, Haas, Brian, Lo, Christopher, Meyers, Robin, Gao, Galen, Cherniack, Andrew, Louissaint, Jr, Abner, Nardi, Valentina, Thorner, Aaron R., Long, Henry, Qiu, Xintao, Morgan, Elizabeth A., Dorfman, David M., Fiore, Danilo, Jang, Julie, Epstein, Alan L., Dogan, Ahmet, Zhang, Yanming, Horwitz, Steven M., Jacobsen, Eric D., Santiago, Solimar, Ren, Jian-Guo, Guerlavais, Vincent, Annis, D. Allen, Aivado, Manuel, Saleh, Mansoor N., Mehta, Amitkumar, Tsherniak, Aviad, Root, David, Vazquez, Francisca, Hahn, William C., Inghirami, Giorgio, Aster, Jon C., Weinstock, David M., and Koch, Raphael

Published
2018
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45. Immune Reconstitution after Double Umbilical Cord Blood Stem Cell Transplantation: Comparison with Unrelated Peripheral Blood Stem Cell Transplantation

Author

Jacobson, Caron A., Turki, Amin T., McDonough, Sean M., Stevenson, Kristen E., Kim, Haesook T., Kao, Grace, Herrera, Maria I., Reynolds, Carol G., Alyea, Edwin P., Ho, Vincent T., Koreth, John, Armand, Philippe, Chen, Yi-Bin, Ballen, Karen, Soiffer, Robert J., Antin, Joseph H., Cutler, Corey S., and Ritz, Jerome

Published
2012
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46. Vitamin A and association with asparaginase-associated pancreatitis in children with acute lymphocytic leukemia.

Author

Tsai, Cheng-Yu, primary, Saito, Toshie, additional, Sarangdhar, Mayur, additional, Abu-El-Haija, Maisam, additional, Wen, Li, additional, Lee, Bomi, additional, Manohar, Murli, additional, Barakat, Monique T., additional, Contrepois, Kévin, additional, Bo, Na, additional, Ding, Ying, additional, Stevenson, Kristen E., additional, Ladas, Elena, additional, Silverman, Lewis B., additional, Quadro, Loredana, additional, Anthony, Tracy G., additional, Jegga, Anil Goud, additional, and Husain, Sohail Z., additional

Published
2022
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50. Molecular map of chronic lymphocytic leukemia and its impact on outcome

Author

Knisbacher, Binyamin A., Lin, Ziao, Hahn, Cynthia K., Nadeu, Ferran, Duran-Ferrer, Marti, Stevenson, Kristen E., Tausch, Eugen, Delgado, Julio, Barbera-Mourelle, Alex, Taylor-Weiner, Amaro, Bousquets-Munoz, Pablo, Diaz-Navarro, Ander, Dunford, Andrew, Anand, Shankara, Kretzmer, Helene, Gutierrez-Abril, Jesus, Lopez-Tamargo, Sara, Fernandes, Stacey M., Sun, Clare, Sivina, Mariela, Rassenti, Laura Z., Schneider, Christof, Li, Shuqiang, Parida, Laxmi, Meissner, Alexander, Aguet, Francois, Burger, Jan A., Wiestner, Adrian, Kipps, Thomas J., Brown, Jennifer R., Hallek, Michael, Stewart, Chip, Neuberg, Donna S., Martin-Subero, Jose, I, Puente, Xose S., Stilgenbauer, Stephan, Wu, Catherine J., Campo, Elias, Getz, Gad, Knisbacher, Binyamin A., Lin, Ziao, Hahn, Cynthia K., Nadeu, Ferran, Duran-Ferrer, Marti, Stevenson, Kristen E., Tausch, Eugen, Delgado, Julio, Barbera-Mourelle, Alex, Taylor-Weiner, Amaro, Bousquets-Munoz, Pablo, Diaz-Navarro, Ander, Dunford, Andrew, Anand, Shankara, Kretzmer, Helene, Gutierrez-Abril, Jesus, Lopez-Tamargo, Sara, Fernandes, Stacey M., Sun, Clare, Sivina, Mariela, Rassenti, Laura Z., Schneider, Christof, Li, Shuqiang, Parida, Laxmi, Meissner, Alexander, Aguet, Francois, Burger, Jan A., Wiestner, Adrian, Kipps, Thomas J., Brown, Jennifer R., Hallek, Michael, Stewart, Chip, Neuberg, Donna S., Martin-Subero, Jose, I, Puente, Xose S., Stilgenbauer, Stephan, Wu, Catherine J., Campo, Elias, and Getz, Gad

Abstract

A genomic, transcriptomic and epigenomic analysis of chronic lymphocytic leukemia identifies genetic drivers and molecular subtypes associated with clinical outcomes. Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

Published
2022

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