Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells
Bin Zhang, … , Wei Tong, Ravi Bhatia
Bin Zhang, … , Wei Tong, Ravi Bhatia
Published February 15, 2016
Citation Information: J Clin Invest. 2016;126(3):975-991. https://doi.org/10.1172/JCI79196.
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Research Article Oncology

Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells

Abstract

Chronic myelogenous leukemia (CML) results from transformation of a long-term hematopoietic stem cell (LTHSC) by expression of the BCR-ABL fusion gene. However, BCR-ABL–expressing LTHSCs are heterogeneous in their capacity as leukemic stem cells (LSCs). Although discrepancies in proliferative, self-renewal, and differentiation properties of normal LTHSCs are being increasingly recognized, the mechanisms underlying heterogeneity of leukemic LTHSCs are poorly understood. Using a CML mouse model, we identified gene expression differences between leukemic and nonleukemic LTHSCs. Expression of the thrombopoietin (THPO) receptor MPL was elevated in leukemic LTHSC populations. Compared with LTHSCs with low MPL expression, LTHSCs with high MPL expression showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro and increased leukemogenic capacity in vivo. Although both G0 and S phase subpopulations were increased in LTHSCs with high MPL expression, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSCs reduced THPO-induced JAK/STAT signaling and leukemogenic potential. These same phenotypes were also present in LTHSCs from patients with CML, and patient LTHSCs with high MPL expression had reduced sensitivity to BCR-ABL tyrosine kinase inhibitor treatment but increased sensitivity to JAK inhibitors. Together, our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSCs and suggest that high MPL–expressing CML stem cells are potential targets for therapy.

Authors

Bin Zhang, Ling Li, Yinwei Ho, Min Li, Guido Marcucci, Wei Tong, Ravi Bhatia

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Figure 8

Sensitivity of human MPLhi LTHSCs to BCR-ABL, JAK, and MEK inhibitors.

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Sensitivity of human MPLhi LTHSCs to BCR-ABL, JAK, and MEK inhibitors. H...
Human CML MPLhi and MPLlo LTHSCs (Lin–CD34+CD38–CD90+) were sorted by flow cytometry and treated with NIL for 3 days. Then, (A) cell growth, (B) CFC, (C) apoptosis, and (D) cell cycle were analyzed. (E) CML MPLhi and MPLlo LTHSCs were cultured with and without THPO in the presence of the JAK inhibitor AZD1480 or the MEK inhibitor PD0325901, and p-ERK, p-STAT3, and p-STAT5 expression was checked by flow cytometry. CML MPLhi and MPLlo LTHSCs were cultured with JAK or MEK inhibitor for 3 days and (F) cell growth, (G) CFC capacity, (H) apoptosis, and (I) cell cycle were checked. *P < 0.05; **P < 0.01; ***P < 0.001. 2-way ANOVA was used to assess significance.