| First Author | Viaud M | Year | 2020 |
| Journal | Cell Rep | Volume | 30 |
| Issue | 10 | Pages | 3397-3410.e5 |
| PubMed ID | 32160545 | Mgi Jnum | J:288284 |
| Mgi Id | MGI:6416737 | Doi | 10.1016/j.celrep.2020.02.056 |
| Citation | Viaud M, et al. (2020) ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms. Cell Rep 30(10):3397-3410.e5 |
| abstractText | 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-3Rbeta 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. |
