The impact of inflammation on HSPC composition and disease progression in chronic myelomonocytic leukemia - Project Summary: Chronic Myelomonocytic Leukemia (CMML) is an aggressive myeloid neoplasm hallmarked by bone marrow dysplasia, cytopenias, peripheral monocytosis, and a propensity for Acute Myeloid Leukemia (AML) transformation. Although uniformly fatal, CMML initially present in a clinically asymptomatic state and is monitored, without treatment, for a period of weeks to months. In all patients, CMML invariably progresses to either a more symptomatic version of disease or undergoes AML transformation. It is this lethal transformation that is responsible for CMML's dismal prognosis and median survival of only 34 months. Importantly, the molecular determinants of progression are poorly understood. CMML disease progression and AML transformation have been historically associated with changes in genetic architecture termed “clonal evolution.” However, a large subset of patients harbor the same somatic mutations and variant allele frequency at the time of progression to that at diagnosis. Our laboratory has discovered a non-clonal evolutionary adaptation whereby leukemic hematopoietic stem cells differentiate to inflammatory GMPs leading to increased fitness in the context of inflammation while maintaining the same repertoire of somatic mutations. Further, this adaptation was associated with adverse outcomes in a retrospective cohort of CMML patients. Last, preclinical inflammatory models of CMML were able to recapitulate this evolutionary adaptation in our preliminary data. Therefore, we hypothesize that inflammatory insults induce the differentiation of leukemic GMPs that are tightly associated with disease progression. This hypothesis will be tested in the following specific aims: (1) Establish the first prospective longitudinal cohort study in CMML. It is very difficult to capture all inflammatory insults via retrospective clinical analysis. To address this, this aim will assemble the first multi-institution prospective longitudinal cohort study of CMML specifically designed to determine whether inflammatory insults are associated with disease progression. Second, we will utilize samples from this study to validate bulk gene expression signatures and a flow-based assay to identify those CMML cases with and inflammatory GMP biased state. Last, we will leverage retrospective cohorts of treated CMML to determine the impact of existing therapy on this GMP biased state. (2) Determine whether the inflammatory GMP biased state is an evolutionary adaptation that can be therapeutically exploited. In this aim, we will use both genetically engineered and patient derived models of CMML to establish the clonal origin of inflammatory GMP, there self-renewing capacity, and the impact of early therapy on this population of cells.
