PMID- 34780648 OWN - NLM STAT- MEDLINE DCOM- 20220307 LR - 20240216 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 139 IP - 5 DP - 2022 Feb 3 TI - MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common beta-chain cytokine receptor endocytosis. PG - 761-778 LID - 10.1182/blood.2021011802 [doi] 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/EBPepsilon axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor but promotes endocytosis of common beta-chain (betac) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade betac 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. CI - (c) 2022 by The American Society of Hematology. FAU - Zhao, Helong AU - Zhao H AD - Versiti Blood Research Institute, Milwaukee, WI. AD - Medical College of Wisconsin, Milwaukee, WI. AD - Division of Hematology and Hematologic Malignancies and. AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Pomicter, Anthony D AU - Pomicter AD AUID- ORCID: 0000-0002-3977-0841 AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Eiring, Anna M AU - Eiring AM AUID- ORCID: 0000-0001-6533-9150 AD - Texas Tech University, El Paso, TX. FAU - Franzini, Anca AU - Franzini A AUID- ORCID: 0000-0003-0359-5399 AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Ahmann, Jonathan AU - Ahmann J AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Hwang, Jae-Yeon AU - Hwang JY AD - Department of Oncological Sciences, The University of Utah, Salt Lake City, UT. FAU - Senina, Anna AU - Senina A AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Helton, Bret AU - Helton B AD - Department of Chemistry, University of Washington, Seattle, WA. FAU - Iyer, Siddharth AU - Iyer S AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Yan, Dongqing AU - Yan D AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Khorashad, Jamshid S AU - Khorashad JS AD - Department of Immunology and Inflammation, Imperial College London, London, United Kingdom. FAU - Zabriskie, Matthew S AU - Zabriskie MS AUID- ORCID: 0000-0003-4240-3484 AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Agarwal, Anupriya AU - Agarwal A AD - Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR. FAU - Redwine, Hannah M AU - Redwine HM AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Bowler, Amber D AU - Bowler AD AUID- ORCID: 0000-0002-9439-2839 AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Clair, Phillip M AU - Clair PM AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - McWeeney, Shannon K AU - McWeeney SK AD - Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR. FAU - Druker, Brian J AU - Druker BJ AUID- ORCID: 0000-0001-8331-8206 AD - Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR. FAU - Tyner, Jeffrey W AU - Tyner JW AD - Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR. FAU - Stirewalt, Derek L AU - Stirewalt DL AD - Fred Hutchinson Cancer Research Center, Seattle, WA; and. FAU - Oehler, Vivian G AU - Oehler VG AD - Fred Hutchinson Cancer Research Center, Seattle, WA; and. FAU - Varambally, Sooryanarayana AU - Varambally S AUID- ORCID: 0000-0002-2277-1127 AD - Department of Pathology, University of Alabama Birmingham, Birmingham, AL. FAU - Berrett, Kristofer C AU - Berrett KC AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Vahrenkamp, Jeffery M AU - Vahrenkamp JM AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. FAU - Gertz, Jason AU - Gertz J AD - Department of Oncological Sciences, The University of Utah, Salt Lake City, UT. FAU - Varley, Katherine E AU - Varley KE AD - Department of Oncological Sciences, The University of Utah, Salt Lake City, UT. FAU - Radich, Jerald P AU - Radich JP AD - Fred Hutchinson Cancer Research Center, Seattle, WA; and. FAU - Deininger, Michael W AU - Deininger MW AUID- ORCID: 0000-0002-2987-1331 AD - Versiti Blood Research Institute, Milwaukee, WI. AD - Medical College of Wisconsin, Milwaukee, WI. AD - Division of Hematology and Hematologic Malignancies and. AD - Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT. LA - eng GR - U42 RR024244/RR/NCRR NIH HHS/United States GR - R01 CA257602/CA/NCI NIH HHS/United States GR - L30 CA171211/CA/NCI NIH HHS/United States GR - S10 RR026802/RR/NCRR NIH HHS/United States GR - R01 CA065823/CA/NCI NIH HHS/United States GR - R01 CA178397/CA/NCI NIH HHS/United States GR - U01 HG004080/HG/NHGRI NIH HHS/United States GR - T32 CA093247/CA/NCI NIH HHS/United States GR - R01 CA229875/CA/NCI NIH HHS/United States GR - U01 HG004085/HG/NHGRI NIH HHS/United States GR - P30 CA042014/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Cell Cycle Proteins) RN - 0 (MS4A3 protein, human) RN - 0 (Membrane Proteins) RN - 0 (Receptors, Cytokine) SB - IM CIN - Blood. 2022 Feb 3;139(5):647-648. PMID: 35113154 MH - Animals MH - Cell Cycle Proteins/genetics/*metabolism MH - Down-Regulation MH - *Endocytosis MH - Gene Expression Regulation, Leukemic MH - Humans MH - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/*metabolism/pathology MH - Membrane Proteins/genetics/*metabolism MH - Mice MH - Receptors, Cytokine/*metabolism MH - Transcriptome MH - Tumor Cells, Cultured PMC - PMC8814676 EDAT- 2021/11/16 06:00 MHDA- 2022/03/08 06:00 PMCR- 2023/02/03 CRDT- 2021/11/15 17:25 PHST- 2021/03/22 00:00 [received] PHST- 2021/10/27 00:00 [accepted] PHST- 2021/11/16 06:00 [pubmed] PHST- 2022/03/08 06:00 [medline] PHST- 2021/11/15 17:25 [entrez] PHST- 2023/02/03 00:00 [pmc-release] AID - S0006-4971(21)01880-2 [pii] AID - 2021/BLD2021011802 [pii] AID - 10.1182/blood.2021011802 [doi] PST - ppublish SO - Blood. 2022 Feb 3;139(5):761-778. doi: 10.1182/blood.2021011802.