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.
Chronic myelogenous leukemia (CML) is propagated by leukemia stem cells (LSC), which resist elimination with available treatments, and persist as a potential source of relapse. We will examine how leukemia cells can induce changes in the CML bone marrow microenvironment that lead to enhanced growth of CML LSC and contribute to their persistence after treatment. Knowledge gained from these studies will help to better understand the role of the leukemic microenvironment in supporting LSC growth and guide development of novel strategies to target LSC.
|Zhang, Bin; Nguyen, Le Xuan Truong; Li, Ling et al. (2018) Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nat Med 24:450-462|
|Bhatia, Ravi (2017) Novel approaches to therapy in CML. Hematology Am Soc Hematol Educ Program 2017:115-120|
|Mesa, Ruben A; Jamieson, Catriona; Bhatia, Ravi et al. (2017) NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018. J Natl Compr Canc Netw 15:1193-1207|
|Agarwal, Puneet; Zhang, Bin; Ho, Yinwei et al. (2017) Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI. Blood 129:1008-1020|
|Zhang, Bin; Chu, Su; Agarwal, Puneet et al. (2016) Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor-treated CML stem cells. Blood 128:2671-2682|
|Irvine, David A; Zhang, Bin; Kinstrie, Ross et al. (2016) Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep 6:25476|
|Zhang, Bin; Li, Ling; Ho, Yinwei et al. (2016) Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells. J Clin Invest 126:975-91|
|Bowers, Marisa; Zhang, Bin; Ho, Yinwei et al. (2015) Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development. Blood 125:2678-88|
|Ågerstam, Helena; Karlsson, Christine; Hansen, Nils et al. (2015) Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proc Natl Acad Sci U S A 112:10786-91|
|Agarwal, Puneet; Bhatia, Ravi (2015) Influence of Bone Marrow Microenvironment on Leukemic Stem Cells: Breaking Up an Intimate Relationship. Adv Cancer Res 127:227-52|
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