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

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.




Enhancer hijacking drives oncogenic BCL11B expression in lineage ambiguous stem cell leukemia.
Authors: Montefiori L.E. , Bendig S. , Gu Z. , Chen X. , Polonen P. , Ma X. , Murison A. , Zeng A. , Garcia-Prat L. , Dickerson K. , et al. .
Source: Cancer Discovery, 2021-06-08 00:00:00.0; , .
EPub date: 2021-06-08 00:00:00.0.
PMID: 34103329
Related Citations

How advanced are we in targeting novel subtypes of ALL?
Authors: Mullighan C.G. .
Source: Best Practice & Research. Clinical Haematology, 2019 12; 32(4), p. 101095.
EPub date: 2019-10-18 00:00:00.0.
PMID: 31779973
Related Citations

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 00:00:00.0.
PMID: 30643249
Related Citations

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 Aug; 17(8), p. 464-470.
PMID: 28842136
Related Citations

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 00:00:00.0; 214(3), p. 773-791.
PMID: 28190000
Related Citations

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 00:00:00.0.
PMID: 27870571
Related Citations

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 Dec; 48(12), p. 1481-1489.
PMID: 27776115
Related Citations

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 00:00:00.0; 7, p. 13331.
PMID: 27824051
Related Citations

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 00:00:00.0; 122(7), p. 1017-28.
PMID: 26849082
Related Citations

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 00:00:00.0; 29(2), p. 186-200.
PMID: 26859458
Related Citations

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 00:00:00.0; 28(3), p. 343-56.
PMID: 26321221
Related Citations

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 00:00:00.0; 125(4), p. 680-6.
PMID: 25468567
Related Citations

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 00:00:00.0; 371(11), p. 1005-15.
PMID: 25207766
Related Citations