Microenvironmental Regulation of Leukemia Stem Cells

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PROJECT SUMMARY ABSTRACT Chronic myelogenous leukemia (CML) results from hematopoietic stem cell (HSC) transformation by the BCR- ABL oncogenic tyrosine kinase. Tyrosine kinase inhibitors (TKI) are highly effective in inducing remission and prolonging survival in CML patients, but do not eliminate primitive, quiescent leukemia stem cells (LSC) responsible for leukemia propagation and regeneration. As a result most patients experience rapid leukemia relapse after TKI discontinuation. However, a subset of patients achieving prolonged, deep remission can successfully discontinue TKI treatment without leukemia recurrence. Our research focuses on understanding mechanisms of LSC resistance to TKI, and development of strategies to target LSC and their microenvironment to prevent leukemia recurrence and enhance treatment free remission (TFR). We now understand that patients achieving TFR continue to harbor small numbers of BCR-ABL+ LSC, suggesting that microenvironmental or immune factor may regulate LSC potential to regenerate leukemia. The bone marrow (BM) microenvironment, which includes diverse hematopoietic and non-hematopoietic cells, plays a critical role in HSC regulation. In contrast, microenvironmental regulation of LSC growth is not well understood. Here we propose to characterize critical niche regulatory mechanisms for maintenance of LSC, and that may contribute to leukemia recurrence after stopping TKI treatment. We have shown that CML development leads to increased levels of several key inflammatory cytokines in the BM, which can provide a selective growth advantage to CML LSC. Our preliminary studies suggest that inflammatory signaling can modify CML BM MSC, resulting in enhanced support for CML LSC, and reduced support of normal HSC. In Aim 1, we will explore the role of TNFa in mediating alterations in BM MSC, resulting in increased expression of the inflammatory chemokine CXCL1 and enhanced signaling through CXCR2 receptor, in LSC maintenance and leukemia regeneration after TKI treatment. Multipotent mesenchymal stromal cells (MSC), identified on the basis of expression of LepR, nestin or Prx1, represent specialized BM niches that maintain normal HSC. Our preliminary studies show that CXCL12 deletion from Prx1+MSC leads to loss of LSC quiescence and enhanced sensitivity to TKI treatment. In Aim 2, we will investigate mechanisms of regulation of LSC cycling and treatment resistance by CXCL12-expressing BM MSC niches, focusing on regulation of EZH2 activity in LSC. We will also study the interaction between CXCL12 and inflammatory signaling in modifying MSC niche function. These studies will be conducted using murine models and primary human CML cells. Better understanding of mechanisms underlying microenvironmental regulation of malignant stem cells will help guide development of novel strategies to enhance TFR in CML patients. We further expect that the results of the proposed research will have broader implication towards other leukemias and solid tumors.