While the majority of children diagnosed with acute lymphoblastic leukemia (ALL) now achieve long term survival on contemporary treatment regimens, more than 20% relapse or die of resistant disease. ALL thus remains the leading cause of cancer death in children. This is particularly true for children diagnosed with 'high-risk"""""""" ALL, accounting for 30% of all cases;outcomes also remain poor in adolescents and adults with ALL. From comprehensive molecular analyses of >900 high-risk ALL cases, we have derived and validated gene expression signatures (""""""""classifiers"""""""") predictive of relapse-free survival (RFS) in ALL and we have discovered novel underlying genetic abnormalities (IKAR0S/IKZF1, JAK, and CRLF2 mutations or genomic rearrangements) that serve as new diagnostic and therapeutic targets for this disease. We now propose to translate these RNA and DNA-based molecular signatures into robust clinical diagnostic tools;complete the validation of the signatures measured in this fashion in a new cohort >500 high-risk ALL patients and develop new algorithms for improved hsk classification, outcome prediction, and therapeutic targeting;and, prospectively test these signatures in the next generation of COG trials.
Our aims are to: 1) refine our microarray-based gene expression classifiers to a final set of predictive genes and translate the quantitative measurement of this multi-analyte signature to a robust clinical diagnostic platform (ABI TaqMan(r) automated, quantitative RT-PCR cards);2) validate the predictive power of this classifier in an independent cohort of 500 high-risk ALL cases relative to the newly defined prognostic molecular abnormalities (involving IKAROS, JAK, CRLF2), and known risk factors (such as minimal residual disease) to develop a new molecular algorithm for risk classification and therapeutic targeting;3) prospectively test the predictive power of the new molecular signatures and risk algorithms in the next generation of COG clinical trials opening in 2011 which will accrue >3000 children with high-risk ALL;and 4) determine the predictive utility of these classifiers, molecular signatures, and risk algorithms in adolescent and young adult ALL patient cohorts as well as older adults with ALL accrued to clinical trials conducted by the adult NCI Cooperative Groups.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-4 (J1))
Program Officer
Jessup, John M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of New Mexico Health Sciences Center
Schools of Medicine
United States
Zip Code
Jain, Nitin; Roberts, Kathryn G; Jabbour, Elias et al. (2017) Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood 129:572-581
Tasian, Sarah K; Teachey, David T; Li, Yong et al. (2017) Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood 129:177-187
Roberts, Kathryn G; Gu, Zhaohui; Payne-Turner, Debbie et al. (2017) High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. J Clin Oncol 35:394-401
Liu, Yu; Easton, John; Shao, Ying et al. (2017) The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 49:1211-1218
Gu, Zhaohui; Churchman, Michelle; Roberts, Kathryn et al. (2016) Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nat Commun 7:13331
Zhang, Jinghui; McCastlain, Kelly; Yoshihara, Hiroki et al. (2016) Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat Genet 48:1481-1489
Larsen, Eric C; Devidas, Meenakshi; Chen, Si et al. (2016) Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232. J Clin Oncol 34:2380-8
Iacobucci, Ilaria; Li, Yongjin; Roberts, Kathryn G et al. (2016) Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia. Cancer Cell 29:186-200
Churchman, Michelle L; Low, Jonathan; Qu, Chunxu et al. (2015) Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer Cell 28:343-56
Ma, Xiaotu; Edmonson, Michael; Yergeau, Donald et al. (2015) Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. Nat Commun 6:6604

Showing the most recent 10 out of 42 publications