dc.contributor.author | Zhao, H | |
dc.contributor.author | Pomicter, AD | |
dc.contributor.author | Eiring, AM | |
dc.contributor.author | Franzini, A | |
dc.contributor.author | Ahmann, J | |
dc.contributor.author | Hwang, J-Y | |
dc.contributor.author | Senina, A | |
dc.contributor.author | Helton, B | |
dc.contributor.author | Iyer, S | |
dc.contributor.author | Yan, D | |
dc.contributor.author | Khorashad, JS | |
dc.contributor.author | Zabriskie, MS | |
dc.contributor.author | Agarwal, A | |
dc.contributor.author | Redwine, HM | |
dc.contributor.author | Bowler, AD | |
dc.contributor.author | Clair, PM | |
dc.contributor.author | McWeeney, SK | |
dc.contributor.author | Druker, BJ | |
dc.contributor.author | Tyner, JW | |
dc.contributor.author | Stirewalt, DL | |
dc.contributor.author | Oehler, VG | |
dc.contributor.author | Varambally, S | |
dc.contributor.author | Berrett, KC | |
dc.contributor.author | Vahrenkamp, JM | |
dc.contributor.author | Gertz, J | |
dc.contributor.author | Varley, KE | |
dc.contributor.author | Radich, JP | |
dc.contributor.author | Deininger, MW | |
dc.date.accessioned | 2022-01-06T14:49:10Z | |
dc.date.available | 2022-01-06T14:49:10Z | |
dc.date.issued | 2022-02-03 | |
dc.identifier.citation | Blood | |
dc.identifier.issn | 0006-4971 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4944 | |
dc.identifier.eissn | 1528-0020 | |
dc.identifier.doi | 10.1182/blood.2021011802 | |
dc.description.abstract | <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> | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | American Society of Hematology | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β-chain cytokine receptor endocytosis | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-10-27 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1182/blood.2021011802 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Blood | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.publication-status | Published online | |
pubs.embargo.terms | Not known | |
dc.contributor.icrauthor | Khorashad, Jamshid | |