Modulating signaling pathways in endothelial cells to abate leukemic progression

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 DESCRIPTION (provided by applicant): The overall goal of this research project is to determine how physiological aging of the bone marrow (BM) vascular niche results in a dysregulation of signaling pathways which leads to the disruption of the cellular cross talk between the BM vascular niche and the hematopoietic stem cell (HSC). In this proposal, we aim to define the mechanisms by which age-related alterations to the BM vascular niche can enhance the progression of hematopoietic malignancies. We have demonstrated that Akt signaling in BM endothelial cells (BMECs) supports the maintenance of the HSCs, whereas age-related increases in Mapk and NF-kB signaling promote the differentiation of HSCs into lineage-committed progeny. Our preliminary data demonstrates that the overexpression of Mapk signaling specifically in ECs leads to premature aging (phenotypic and functional) of the HSC and that inhibiting NF-kB signaling in Akt-activated ECs results in a robust in vivo expansion of functional HSCs thereby enhancing hematopoietic recovery following myelosuppression. Additionally, we have found that Akt, Mapk, and NF-kB signaling are upregulated in in vivo BMECs when in contact with AML cells and that Akt-activation in ECs can expand phenotypic leukemia initiating cells leading to aggressive disease. Based on this evidence, we hypothesize that disruption of key signaling pathways in aged BMECs deprive the hematopoietic system from EC-derived instructive signals that are essential for the maintenance and regeneration of non-malignant hematopoietic cells. To formally address this hypothesis, our laboratory has devised novel in vivo and in vitro models that will allow us to determine if modulation of endothelial-specific signaling pathways can "safe guard" normal HSCs while increasing the susceptibility of the leukemic cells to chemotherapeutic regimens, effectively giving a competitive advantage to the non-malignant hematopoietic system. Utilizing our in vivo mouse models and ex vivo instructive mouse EC/HSC co-culture system that can be utilized to assess the growth potential and aggressiveness of leukemic cells grown on various BMEC lines, we will be able to test 1) if aged BMECs and aberrantly activated (Mapk) BMECs can support the outgrowth of aggressive leukemic clones, 2) if modulation of the Akt/NF-kB signaling axis can reverse age-related hematopoietic defects and give a competitive advantage to non-malignant hematopoietic cells at steady state and following chemotherapeutic intervention, and 3) whether the activation state of the BM endothelium drive the onset of AML using an in vivo genetic mouse model of AML. These studies will begin to unravel the mechanisms by which dysregulation of BMECs in an aged BM microenvironment can lose their instructive capacity to support the proper balance between HSC self-renewal and differentiation. The success of these studies may potentially open up new avenues for the development of a wide array of therapeutic strategies designed as an effective means to diminish leukemic burden and minimal residual disease by augmenting the sensitivity of leukemic cells to chemotherapeutic regimens.