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Microenvironmental Regulation of Leukemia Stem Cells

Ravi Bhatia

1 Collaborator(s)

Funding source

National Cancer Institute (NIH)
Chronic myelogenous leukemia (CML) is a lethal hematological malignancy that results from transformation of long-term hematopoietic stem cells (LTHSC) to leukemia stem cells (LSC) by the BCR-ABL gene. BCR- ABL tyrosine kinase inhibitors (TKI) are effective in inducing disease remission in CML patients and prolonging survival, but do not eliminate LSC responsible for disease propagation. CML patients currently require indefinite treatment with TKI to prevent disease recurrence, with associated risk of non-compliance, side effects, and considerable financial burden. There is a pressing need to develop strategies to target LSC to enable cessation of TKI treatment without leukemia recurrence. The major goal of our research is to achieve improved understanding of mechanisms regulating LSC growth to develop effective therapeutic strategies to target this resistant population. Our previous studies to characterize LSC in CML indicate that long-term engraftment and LSC capacity are restricted to cells with LTHSC surface markers. We have shown that, in addition to BCR-ABL induced alterations in LTHSC function, leukemia-induced alterations in the BM microenvironment results in differential regulation of leukemic and normal LTHSC, conferring a competitive growth advantage to leukemic LTHSC. Our results indicate that decreased expression of the chemokine CXCL12 by CML BM mesenchymal cells, in addition to contributing to reduced LTHSC homing and retention, may also support enhanced expansion of CML compared to normal LTHSC. We have also found that the pro-inflammatory cytokine IL-1? is overexpressed in CML BM, and that IL-1 signaling supports enhanced proliferation of CML compared to normal LTHSC. Abnormalities in BM microenvironmental regulation are improved but not completely corrected with TKI treatment. Here we will determine the contribution of these specific abnormalities in the CML BM microenvironment to the competitive growth advantage of CML LTHSC, and to the persistence of leukemic LTHSC after TKI treatment. In Specific Aim 1, we will examine mechanisms underlying reduced CXCL12 expression in CML BM mesenchymal subpopulations, and determine the role of reduced CXCL12 expression in the enhanced growth of CML compared to normal LTHSC in CML BM and in persistence of CML LTHSC following TKI treatment. In Specific Aim 2 we will examine mechanisms underlying IL-1? overexpression in CML BM following TKI treatment, and determine the role of IL-1? overexpression in enhanced growth of CML compared to normal LTHSC in CML BM and in persistence of CML LTHSC following TKI treatment. These studies will be performed using samples from CML patients as well as the SCL-tTA-BCR-ABL mouse model. The results of these studies will improve our understanding of interactions between leukemia cells and the BM microenvironment that regulate leukemic and normal LTHSC growth, and may guide development of novel strategies to enhance LSC targeting to achieve disease elimination and cure.

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