Molecular Mechanisms of MDS pathogenesis with aging

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Project Summary/Abstract In the last decade, significant efforts have been made to understand the development and complexity of Myelodysplastic syndromes (MDS), leading to the identification of recurrently mutated genes with well-defined clinical, prognostic, and therapeutic implications. However, this has not been translated yet in effective treatments. MDS can arise from a small population of disease-initiating cells that are not eliminated by conventional therapies. An improved understanding of the molecular pathways that regulate these disease initiating stem cells is paramount for the development of future curative therapies. Several factors converge to induce evolution of malignant cells. Using 3 mouse models of MDS (the β-catenin-induced, the NUP98-HOXD13- induced and the PU.1UREhetMsh2–/– -induced MDS models) and patient cells (MDS and paired MDS to transformed AML) we have identified a transcriptional signature that is highly associated with MDS induction and disease transformation. This signature comprises decreased expression of Nucleoporin (NUPs) family members in AML as compared to MDS cells. NUPs expression is also downregulated in MDS cells as compared to healthy HSCs in humans and inversely correlates with DNMT3A mutations, that are prominent in age-related clonal hematopoiesis (ARCH), in AML cases transformed from previous MDS. In mouse and human iPSC models of MDS, decreasing NUPs expression induces transformation of MDS cells to AML blasts. Our goal in this application is to comprehensively examine the role of the NUP pathway in the induction of MDS from aging related factors of clonal hematopoiesis and inflammation and in MDS stem cell dynamics and identify the driving factors and mechanisms of their actions. To achieve this, we will define the mechanism through which NUPs downregulation affects the growth of disease initiating stem cells in MDS; determine the requirement of a decrease in NUPs expression for MDS initiation with aging and aging- related factors of ARCH and inflammatory stress; and determine how NUPs promote clonal heterogeneity by defining the genetic, molecular and transcriptional mechanisms of NUP-related MDS evolution with aging. These studies will identify mechanisms and molecules that are significant contributors to MDS pathogenesis and which may be therapeutically and preventatively targeted.