Building on our success as world leaders in acute lymphoblastic leukemia (ALL) and as leaders in the Pharmacogenomics Research Network (PGRN), we have formed a Center for Precision Medicine in Leukemia. Our goal is to identify the mechanisms underlying interpatient variability in response to antileukemia medications. We will integrate state-of-the-art genomic, transcriptomic, and epigenomic interrogation of somatic cell ALL tumor cells, host germline DNA variation, and comprehensive assessment of treatment variables and non-genetic features in children and adults with ALL, coupled with laboratory mechanistic studies, to identify sources and mechanisms of interpatient variation in response. Many ALL medications are also used to treat other pediatric and adult cancers and also nonmalignant diseases: for example, glucocorticoids, methotrexate, and thiopurines are commonly used for nonmalignant diseases such as asthma, autoimmune, and inflammatory diseases, and so ALL can serve as a model for how to optimize use of therapy that will have broad implications beyond ALL. Our investigators include leaders in adult and childhood ALL, pharmacogenomics, human genomics, clinical pharmacology, computational biology, bioinformatics, and biostatistics. We have three major aims, addressed in three highly integrated projects (all of which capitalize on front-line ALL clinical trials) and three Center cores. In Proect 1, we will define the landscape of genome variation among ALL subtypes and identify the inherited and somatically acquired genomic variation, along with other clinical features, that are associated with ALL treatment response in patients. In Project 2, we will identify the genome variation associated with de novo and acquired drug resistance in primary ALL cells from patients at diagnosis and at relapse, and will elucidate mechanisms by which genomic variation influences drug resistance and treatment response. In Project 3, we will identify genomic variation associated with specific serious adverse effects of antileukemic agents (osteonecrosis, hepatotoxicity, pancreatitis, and neuropathy), establishing mechanisms and testing interventions for the phenotype of osteonecrosis. Synergies in the Center stem from the substantial overlap in patients and genomic data among the three projects; the complementary expertise and prior collaborations among investigators; the leadership of our Administrative Core with extensive ties to existing pharmacogenomic, genomic, and clinical cancer networks; and uniform approaches to data analysis, management, integration, and deposition provided by our Cores. Our Center's overarching aim is to use the knowledge gained from the research in the three projects to build a comprehensive precision medicine approach to minimize relapse while also minimizing adverse effects. This Center will allow us to engage additional adult ALL and genomics collaborators, accelerate progress in the discovery and translation of genomics into more effective and less toxic treatments, and provide a paradigm for other diseases for the integration of genomic methods and knowledge into precision medicine.

Public Health Relevance

Acute lymphoblastic leukemia is the most common tumor in children and is very responsive to medications, but outcomes are much worse in adults. This center identifies the genetic and non-genetic risk factors for tumor relapse and for serious adverse effects of the medications, and will build new models for how to precisely match patients to medication regimens to maximize cure and minimize adverse effects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Long, Rochelle M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Jude Children's Research Hospital
United States
Zip Code
Nishii, Rina; Moriyama, Takaya; Janke, Laura J et al. (2018) Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy. Blood 131:2466-2474
Pui, Ching-Hon; Liu, Yiwei; Relling, Mary V (2018) How to solve the problem of hypersensitivity to asparaginase? Pediatr Blood Cancer 65:
Zhang, Yingchi; Gao, Yufeng; Zhang, Hui et al. (2018) PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia. Blood 131:2256-2261
Gupta, Sumit; Devidas, Meenakshi; Loh, Mignon L et al. (2018) Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group (COG). Leukemia 32:1370-1379
Steeghs, Elisabeth M P; Bakker, Marjolein; Hoogkamer, Alex Q et al. (2018) High STAP1 expression in DUX4-rearranged cases is not suitable as therapeutic target in pediatric B-cell precursor acute lymphoblastic leukemia. Sci Rep 8:693
Diouf, Barthelemy; Lin, Wenwei; Goktug, Asli et al. (2018) Alteration of RNA Splicing by Small-Molecule Inhibitors of the Interaction between NHP2L1 and U4. SLAS Discov 23:164-173
Pui, Ching-Hon (2018) To delay or not to delay, that is the question for patients with acute lymphoblastic leukemia who do not receive prophylactic cranial irradiation. Cancer 124:4442-4446
Churchman, Michelle L; Qian, Maoxiang; Te Kronnie, Geertruy et al. (2018) Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell 33:937-948.e8
Browne, Emily K; Zhou, Yinmei; Chemaitilly, Wassim et al. (2018) Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia. Cancer 124:4248-4259
Diouf, Barthelemy; Evans, William E (2018) Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy: Progress Continues. Clin Pharmacol Ther :

Showing the most recent 10 out of 72 publications