MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis

Helong Zhao, Anthony D. Pomicter, Anna M. Eiring, Anca Franzini, Jonathan Ahmann, Jae Yeon Hwang, Anna Senina, Bret Helton, Siddharth Iyer, Dongqing Yan, Jamshid S. Khorashad, Matthew S. Zabriskie, Anupriya Agarwal, Hannah M. Redwine, Amber D. Bowler, Phillip M. Clair, Shannon K. McWeeney, Brian J. Druker, Jeffrey W. Tyner, Derek L. StirewaltVivian G. Oehler, Sooryanarayana Varambally, Kristofer C. Berrett, Jeffery M. Vahrenkamp, Jason Gertz, Katherine E. Varley, Jerald P. Radich, Michael W. Deininger

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by the excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase (BP). Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor but promotes endocytosis of common β-chain (βc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade βc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown (KD) or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhances leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and BP-CML. Promoting MS4A3 reexpression or delivery of ectopic MS4A3 may help eliminate LSPCs in vivo.

Original languageEnglish (US)
Pages (from-to)761-778
Number of pages18
Issue number5
StatePublished - Feb 3 2022

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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