Integrated Systems Biology of Pediatric AML

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ABSTRACT: Acute myeloid leukemia (AML) is a rare, devastating, and understudied malignancy with ~20,00 new cases and around 61,000 cases in US. Though intensive chemotherapy primarily consisting of ara C (also known as cytarabine), daunorubicin, and etopside have been used to treat AML for over 4 decades, only 65%, 40%, and 10% of pediatric (age <21), adult (age 21-65), and elderly (age > 65) patients survive 5 years after diagnosis, respectively. Application co-PIs, Drs. Lamba (pharmacology) and Pounds (biostatistician specializing in cancer genomics) have successfully collaborated for over a decade to develop methods and discover molecular prognostic factors for AML. We and other investigators from Children’s Oncology group have recently characterized the genome, methylome, and transcriptome of pediatric AML and associated each of these with prognosis in pediatric AML. Dr. Pounds developed the innovative integrative analysis procedure, canonical correlation with projection onto the most interesting statistical evidence (CC-PROMISE), that dramatically increases statistical power for meaningful biological discovery in a rare-disease small sample size setting; using CC-PROMISE, we discovered that reduced methylation and increased expression of the DNMT3B associates with greater genome-wide methylation burden and worse prognosis; translating the DNMT3B discovery into evaluation of demethylating agents in the ongoing AML16 clinical trial (NCT03164057). These genomic, epigenomic, and transcriptomic features, along with microenvironmental and other factors, must impact the proteome and metabolome of AML in clinically relevant ways which unfortunately are not well understood. There has been essentially no study focused on comprehensive evaluation of the proteome and metabolome of pediatric AML in a reasonable cohort of uniformly treated patients. Noting the marked genomic, transcriptomic, methylomic, and prognostic differences between pediatric and adult AML, it is not plausible to extrapolate finding from adult AML patients to pediatric. Thus an integrated systems-level understanding of the molecular disease biology is needed to develop effective strategies and improve the prognosis of pediatric AML. As pioneers in the collection and integrated analysis of the pediatric AML genome, methylome, and transcriptome, application co-PIs Drs. Lamba and Pounds are uniquely positioned to characterize the proteome and metabolome of pediatric AML and integrate them with our large repository of previously collected molecular, treatment, and outcome data for a series of multi-center clinical trials. Thus, in this application we propose to characterize global metabolome (aim 1) and proteome (aim 2) the leukemic cell obtained at diagnosis for risk stratification and prognosis by evaluating impact on outcome in three St Jude led multi-institute clinical trials (AML02, AML08 and AML16, total patients n=400). In aim 3, we plan to develop a comprehensive integrated view of the genome, methylome, transcriptome, proteome, metabolome, and clinical prognosis of pediatric AML using novel methods. These innovative and exceptionally rigorous studies will be the first comprehensive evaluation of the pediatric AML metabolome and proteome and develop an innovative integrated analysis method to perform the first integrated analysis of five forms of omic data with multiple clinical endpoints to obtain the most complete understanding of pediatric AML systems biology to date.