MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis
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Date
2022-02-03ICR Author
Author
Zhao, H
Pomicter, AD
Eiring, AM
Franzini, A
Ahmann, J
Hwang, J-Y
Senina, A
Helton, B
Iyer, S
Yan, D
Khorashad, JS
Zabriskie, MS
Agarwal, A
Redwine, HM
Bowler, AD
Clair, PM
McWeeney, SK
Druker, BJ
Tyner, JW
Stirewalt, DL
Oehler, VG
Varambally, S
Berrett, KC
Vahrenkamp, JM
Gertz, J
Varley, KE
Radich, JP
Deininger, MW
Type
Journal Article
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Show full item recordAbstract
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>
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Language
eng
Date accepted
2021-10-27
Citation
Blood
Publisher
American Society of Hematology