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Grant Details

Grant Number: 5RC1CA145707-02 Interpret this number
Primary Investigator: Mullighan, Charles
Organization: St. Jude Children'S Research Hospital
Project Title: Genomic Analysis of Adolescent and Young Adult Acute Lymphoblastic Leukemia
Fiscal Year: 2010
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Abstract

DESCRIPTION (provided by applicant): Challenge Area: 15: Translational Science Challenge Topic: 15-CA-105: The Biology of Cancer in Adolescents and Young Adults. Project title: Genomic Analysis of Adolescent and Young Adult Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is one of the leading causes of cancer related death in the adolescent and young adult (AYA) population. Relative to younger children with ALL, the overall outcomes in AYA ALL are significantly poorer. Whether these outcome differences are due to distinct underlying genetic and biologic features or different therapeutic approaches remain to be determined. Studies examining the underlying biologic and genetic basis of AYA ALL, and comparison to younger children who have been extensively studied and older adults, are urgently required to (1) determine the spectrum and variation of distinct ALL-associated genetic alterations in different age groups and their prognostic importance, and (2) to identify novel therapeutic targets. We have recently performed detailed genomic characterization of standard and high risk pediatric ALL using complementary gene expression profiling, genome-wide analysis of genetic alterations, and targeted gene resequencing. Through these efforts we have identified multiple novel genomic alterations that perturb key cellular pathways and which are associated with significant differences in the outcome of therapy. Importantly, candidate gene resequencing has also identified novel kinase mutations in children with high risk ALL that represent novel targets for therapy. In our studies of over 1000 children, we have studied over 50 patients at the younger age end of the AYA spectrum (age 16-21). Interestingly these AYA ALL cases appear to have underlying genetic and biologic features more commonly seen in higher risk forms of pediatric ALL, including genetic alteration of the lymphoid transcription factor IKAROS, mutation of JAK kinases, and a gene expression signature associated with an extremely poor outcome. These findings suggest that a comparably detailed genomic analysis of a large cohort of AYA ALL patients is likely to yield critical insights into the poor outcome of this unique group patients, and also may identify novel therapeutic targets. This study will perform complementary gene expression profiling, genome-wide analysis of DNA copy number alterations, and candidate gene resequencing in a large cohort of AYA ALL cases. Four hundred cases spanning the age range of AYA ALL will be studied, using existing AYA ALL samples with associated clinical, phenotypic and outcome data from the NCI Cooperative Oncology Groups. This will enable the first integrated genomic analysis of AYA ALL. The complementary approaches will permit: (1) identification of recurring DNA copy number alterations in AYA ALL, and correlation with effects on local and global gene expression patterns; (2) identification of gene expression signatures that correlate with outcome; (3) pathway analysis of genomic data to identify cellular pathways involved by genomic alterations; and (4) identification of sequence mutations in genes known to be mutated in pediatric ALL, and also in novel targets of genomic alteration in the AYA ALL cohort. The principle investigators have extensive experience in the implementation of these approaches and analysis of the resulting data in large ALL datasets. Through a joint NCI TARGET project in high risk pediatric ALL, they have collaborated extensively and jointly published over the past two years. Importantly, all data resulting from this project will be made publicly available through The NCI Cancer Genome Workbench to facilitate public dissemination of the results. This project will provide an invaluable opportunity to better characterize the biology of AYA ALL and determine the reasons for treatment failure. Ultimately, these data will for the foundation for studies characterizing novel therapeutic approaches in this disease. PUBLIC HEALTH RELEVANCE: Acute lymphoblastic leukemia (ALL) is a leading cause of cancer-related death in adolescents and young adults (AYA). In contrast to children with ALL, for whom survival rates now exceed 80%, the outcome of treatment in AYA ALL is poor. The reasons why the outcome of AYA ALL is worse than in children are poorly understood. We have previously examined the genetic features in large numbers of childhood ALL tumor samples using detailed genomic profiling, and have identified new genetic alterations that predict prognosis, and have also identified new targets for treatment. We now wish to perform similar analyses in AYA ALL, with the aims of improving our understanding the biology of the disease, our understanding of the genetic determinants of treatment outcome, indentifying new treatment targets, and ultimately improving outcome. This study offers the opportunity to provide important insights and advances in one of the leading causes of AYA death.

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Publications

PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.
Authors: Gu Z. , Churchman M.L. , Roberts K.G. , Moore I. , Zhou X. , Nakitandwe J. , Hagiwara K. , Pelletier S. , Gingras S. , Berns H. , et al. .
Source: Nature genetics, 2019 02; 51(2), p. 296-307.
EPub date: 2019-01-14.
PMID: 30643249
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Philadelphia Chromosome-like Acute Lymphoblastic Leukemia.
Authors: Pui C.H. , Roberts K.G. , Yang J.J. , Mullighan C.G. .
Source: Clinical lymphoma, myeloma & leukemia, 2017 08; 17(8), p. 464-470.
PMID: 28842136
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Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome.
Authors: Witkowski M.T. , Hu Y. , Roberts K.G. , Boer J.M. , McKenzie M.D. , Liu G.J. , Le Grice O.D. , Tremblay C.S. , Ghisi M. , Willson T.A. , et al. .
Source: The Journal of experimental medicine, 2017-03-06; 214(3), p. 773-791.
EPub date: 2017-02-11.
PMID: 28190000
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High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults.
Authors: Roberts K.G. , Gu Z. , Payne-Turner D. , McCastlain K. , Harvey R.C. , Chen I.M. , Pei D. , Iacobucci I. , Valentine M. , Pounds S.B. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017 Feb; 35(4), p. 394-401.
EPub date: 2016-11-21.
PMID: 27870571
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Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.
Authors: Gu Z. , Churchman M. , Roberts K. , Li Y. , Liu Y. , Harvey R.C. , McCastlain K. , Reshmi S.C. , Payne-Turner D. , Iacobucci I. , et al. .
Source: Nature communications, 2016-11-08; 7, p. 13331.
EPub date: 2016-11-08.
PMID: 27824051
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Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.
Authors: Zhang J. , McCastlain K. , Yoshihara H. , Xu B. , Chang Y. , Churchman M.L. , Wu G. , Li Y. , Wei L. , Iacobucci I. , et al. .
Source: Nature genetics, 2016 12; 48(12), p. 1481-1489.
EPub date: 2016-10-24.
PMID: 27776115
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Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma.
Authors: Tricoli J.V. , Blair D.G. , Anders C.K. , Bleyer W.A. , Boardman L.A. , Khan J. , Kummar S. , Hayes-Lattin B. , Hunger S.P. , Merchant M. , et al. .
Source: Cancer, 2016-04-01; 122(7), p. 1017-28.
EPub date: 2016-02-05.
PMID: 26849082
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Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia.
Authors: Iacobucci I. , Li Y. , Roberts K.G. , Dobson S.M. , Kim J.C. , Payne-Turner D. , Harvey R.C. , Valentine M. , McCastlain K. , Easton J. , et al. .
Source: Cancer cell, 2016-02-08; 29(2), p. 186-200.
PMID: 26859458
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Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia.
Authors: Churchman M.L. , Low J. , Qu C. , Paietta E.M. , Kasper L.H. , Chang Y. , Payne-Turner D. , Althoff M.J. , Song G. , Chen S.C. , et al. .
Source: Cancer cell, 2015-09-14; 28(3), p. 343-56.
EPub date: 2015-08-27.
PMID: 26321221
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A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.
Authors: Perez-Andreu V. , Roberts K.G. , Xu H. , Smith C. , Zhang H. , Yang W. , Harvey R.C. , Payne-Turner D. , Devidas M. , Cheng I.M. , et al. .
Source: Blood, 2015-01-22; 125(4), p. 680-6.
EPub date: 2014-12-02.
PMID: 25468567
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Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
Authors: Roberts K.G. , Li Y. , Payne-Turner D. , Harvey R.C. , Yang Y.L. , Pei D. , McCastlain K. , Ding L. , Lu C. , Song G. , et al. .
Source: The New England journal of medicine, 2014-09-11; 371(11), p. 1005-15.
PMID: 25207766
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