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

The Journal of Clinical Investigation
Bin ZhangRavi Bhatia

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 ex...Continue Reading

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Citations

Dec 27, 2016·Experimental Hematology·Cassie J Clarke, Tessa L Holyoake
Dec 10, 2016·Blood·Delphine ReaUNKNOWN France Intergroupe des Leucémies Myéloïdes Chroniques
Feb 6, 2017·Blood·Tessa L Holyoake, David Vetrie
Mar 10, 2017·Expert Opinion on Drug Discovery·Gillian A Horne, Mhairi Copland
Nov 16, 2017·Blood·Elodie GrockowiakVéronique Maguer-Satta
Aug 7, 2018·Journal of Cellular and Molecular Medicine·Gabriela Flores-LopezAntonieta Chávez-González
Jan 18, 2018·Leukemia & Lymphoma·Jieke CuiPing Zou
Dec 10, 2017·Hematology·Ravi Bhatia
Apr 25, 2019·Stem Cells Translational Medicine·Haojian Zhang, Shaoguang Li
Jan 8, 2020·Nature Reviews. Cancer·David VetrieMhairi Copland
Jul 20, 2019·Cancer Biomarkers : Section a of Disease Markers·Shan WangZheng Hu
Jul 10, 2017·International Journal of Hematology·Delphine Rea, Jean-Michel Cayuela
May 10, 2019·Proceedings of the National Academy of Sciences of the United States of America·Leyuan MaMichael R Green
Feb 9, 2017·International Journal of Hematology·Virginia CamachoRobert S Welner
May 7, 2021·Nature Reviews. Cancer·Andrew E WhiteleyDorothy A Sipkins

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Datasets Mentioned

BETA
GSE76123

Methods Mentioned

BETA
transgenic
flow cytometry
xenograft
RNA-Seq

Software Mentioned

cBot
GSEA
DAVID Bioinformatics Resources
GraphPad
Bioconductor ShortRead
Prism
Bioconductor EdgeR package
Real
DAVID
time analysis

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