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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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 7

Human CML MPLhi LTHSCs show enhanced proliferative and regenerative capacity.

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Human CML MPLhi LTHSCs show enhanced proliferative and regenerative capa...
(A) MPL expression in human normal and CML CD34+CD38–CD90+ LTHSCs analyzed by flow cytometry. (B) Cell growth, (C) CFC, (D) apoptosis of normal and CML MPLhi and MPLlo LTHSCs cultured in SFEM medium for 72 hours with or without THPO (10 ng/ml). (E and F) Cell cycling of CML and normal MPLhi and MPLlo LTHSCs cultured in SFEM medium for 72 hours in the presence of THPO (10 ng/ml). Combined results of p-STAT3 and p-STAT5 expression by flow cytometry in (G and H) normal and (I and J) CML MPLhi and MPLlo LTHSCs in the presence of THPO (10 ng/ml) (n = 4). Normal and CML MPLhi and MPLlo LTHSCs were sorted and transplanted into NSG mice. Engraftment of human CD45+ cells in PB, BM, and spleens at 4 weeks and 16 weeks from (M and N) normal and (K and L) CML LTHSCs. Results represent mean ± SEM of results from 4 to 13 patients with CML. *P < 0.05; **P < 0.01; ***P < 0.001. 2-way ANOVA was used to assess significance.