Clinical and Molecular Heterogeneity in the Myelodysplastic Syndromes

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SUMMARY MDS represents a group of acquired bone marrow failure syndromes arising from hematopoietic stem cells (HSCs). While most MDS patients experience progressive cytopenias, a significant minority (30%) will progress to acute myeloid leukemia (AML); however, the mechanisms that determine whether patients experience progressive cytopenias or leukemia transformation are poorly understood. While the ineffectiveness of MDS therapies is due to their inability to effectively eliminate MDS clones and/or restore normal differentiation, it remains unclear whether hypomethylating agents (HMAs) act on HSCs or committed progenitors to induce hematologic improvement and/or reductions in blast count, or if HMAs act through similar or unique mechanisms in these distinct cell populations. We and others have shown that MDS HSCs exhibit markedly different gene expression profiles than CD34+ hematopoietic stem/progenitor cells (HSPCs) and that they are also genetically and transcriptionally heterogeneous6-10; however, these prior studies were not designed to specifically capture committed progenitor contributions to disease progression or therapeutic responses to HMAs. We hypothesize that HSCs and committed progenitors from MDS patients who experience progressive cytopenias or leukemic transformation exhibit unique transcriptional signatures prior to, and in response to, HMA therapy. Secondarily, we hypothesize that HMAs induce unique transcriptional and functional changes in MDS HSCs and committed progenitors, and that their ability to induce specific transcriptional programs determines whether or not patients respond with hematologic improvements and/or blast reductions. We propose to elucidate the transcriptional basis of HSC and committed progenitor responses from MDS patients at the single cell level using novel full-length cDNA scRNA-seq technologies that will allow simultaneous characterization of the transcriptome and mutational data within individual cells from paired pre- and post-therapy samples from MDS patients with different types of disease progression and responses to HMA therapy. We also will evaluate the clinical relevance of our findings by evaluating MDS-associated RNA features in larger cohorts of MDS patients for whom transcriptome data and clinical outcome data are available. Assessments of the contribution of dysregulated transcripts to MDS progression will be evaluated using mouse models of MDS as well as primary MDS patient cells. Overall, we expect our studies to: 1) Identify the genes and biological pathways that determine whether MDS patients will experience progressive cytopenia versus leukemic transformation; 2) Elucidate the roles of different HSPC populations in determining clinical responses to HMA therapy; 3) Identify novel biomarkers for prognostication of clinical outcomes and therapy responses in MDS; 4) Provide the biological rationale for future clinical studies of novel pathway- or genetically-targeted agents in combination with HMAs.