TY - JOUR
T1 - MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis
AU - Zhao, Helong
AU - Pomicter, Anthony D.
AU - Eiring, Anna M.
AU - Franzini, Anca
AU - Ahmann, Jonathan
AU - Hwang, Jae Yeon
AU - Senina, Anna
AU - Helton, Bret
AU - Iyer, Siddharth
AU - Yan, Dongqing
AU - Khorashad, Jamshid S.
AU - Zabriskie, Matthew S.
AU - Agarwal, Anupriya
AU - Redwine, Hannah M.
AU - Bowler, Amber D.
AU - Clair, Phillip M.
AU - McWeeney, Shannon K.
AU - Druker, Brian J.
AU - Tyner, Jeffrey W.
AU - Stirewalt, Derek L.
AU - Oehler, Vivian G.
AU - Varambally, Sooryanarayana
AU - Berrett, Kristofer C.
AU - Vahrenkamp, Jeffery M.
AU - Gertz, Jason
AU - Varley, Katherine E.
AU - Radich, Jerald P.
AU - Deininger, Michael W.
N1 - Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/2/3
Y1 - 2022/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123891152&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123891152&partnerID=8YFLogxK
U2 - 10.1182/blood.2021011802
DO - 10.1182/blood.2021011802
M3 - Article
C2 - 34780648
AN - SCOPUS:85123891152
SN - 0006-4971
VL - 139
SP - 761
EP - 778
JO - Blood
JF - Blood
IS - 5
ER -