| Autor: |
Manon Viaud, Omar Abdel-Wahab, Julie Gall, Stoyan Ivanov, Rodolphe Guinamard, Sophie Sore, Johanna Merlin, Marion Ayrault, Emma Guilbaud, Arnaud Jacquel, Patrick Auberger, Nan Wang, Ross L. Levine, Alan R. Tall, Laurent Yvan-Charvet |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 30, Iss 10, Pp 3397-3410.e5 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2020.02.056 |
| Popis: |
Summary: Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis. : Viaud et al. show that ABCA1 mutants identified in CMML patients diminish the tumor-suppressor functions of ABCA1 and cooperate with Tet2 loss to confer the hypersensitivity of myeloid progenitors to IL-3 receptor β canonical signaling, which can be prevented by raising HDL levels. Keywords: somatic mutations, leukemia biology, ATP-binding cassette transporter, cholesterol efflux, hematopoietic stem and progenitor cells, ten-eleven translocation 2 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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