Defining the biological consequences of somatic mutations in high risk AML using integrative single cell approaches

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Project Summary Acute Myeloid Leukemia (AML) is an aggressive blood cancer with exceedingly poor patient outcomes. Systematic sequencing studies in myeloid neoplasms have identified the recurrent mutations in AML, raising opportunities for the development of targeted therapeutics (e.g. IDH1/2 and FLT3) and molecularly guided clinical care (diagnosis, risk stratification). Despite these recent advances, how these mutations specifically drive pathogenesis and disease progression and define treatment responses is less well understood. Definition of these relationships has been challenged by the genetic and clonal diversity of AML genomes. This proposal aims to study the biological and clinical role of acquired mutations in two complementary contexts: 1) IDH1/2 mutant AML at diagnosis and under IDH inhibitor therapy (targeted therapeutics); 2) TP53 mutant clonal hematopoiesis transformation to AML under cytotoxic therapy for solid tumors (early detection and intervention). To address this question, we established a method to derive single cell genotype and gene expression. We show we can assign single cells to subclones and deliver subclone-specific gene expression profiles in AML. Targeted inhibitors for IDH1 and IDH2 mutations recently attained FDA approval in relapsed/refractory AML, however response remains highly variable. In these clinical trials, patients with subclonal mutations in signaling or splicing genes were more likely to be non-responders. The first specific aim is to define the role of acquired mutations in IDH1/2-mutant AML at diagnosis and under IDH inhibitor therapy using integrative single cell approaches. We hypothesize that the biological effectors of signaling and splicing mutations drive subclonal gene expression profiles mediating resistance, distinct from the inhibitor-sensitive dominant clone. Our preliminary data identifies mutations in TP53 at clonal hematopoiesis are associated with subsequent acquisition of allelic imbalances and transformation to AML under chemotherapy for solid tumors. The second specific aim is to study mechanisms of TP53 mutant clonal hematopoiesis transformation to therapy-related myeloid neoplasm using integrative single cell approaches. We will test the hypothesis that TP53 mutations provide fertile ground for allelic imbalances and these aberrations together drive progression to AML. Together, these aims inform how individual mutations contribute to myeloid pathogenesis during disease initiation, progression, and under the selective pressure of treatment. This will provide insight into AML disease biology, clinical response, and the development of new early detection and therapeutic strategies. Dr. Elli Papaemmanuil and Dr. Ross Levine, with expertise in the functional and clinical consequences of somatic mutations in myeloid malignancies, serve as Sponsors of this application. The Gerstner Sloan Kettering Graduate School provides the optimal training environment for the applicant. This training will advance the applicant’s goal to become a principal investigator on the frontier of cancer biology and genomics.