ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms.
ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms.
复制标题
ABCA1 在骨髓增生性肿瘤中发挥肿瘤抑制功能。
DOI：
10.1016/j.celrep.2020.02.056
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Yvan-Charvet,Laurent
中科院分区：
文献类型：
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作者：
Viaud,Manon;Abdel-Wahab,Omar;Gall,Julie;Ivanov,Stoyan;Guinamard,Rodolphe;Sore,Sophie;Merlin,Johanna;Ayrault,Marion;Guilbaud,Emma;Jacquel,Arnaud;Auberger,Patrick;Wang,Nan;Levine,RossL;Tall,AlanR;Yvan-Charvet,Laurent
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 inABCA1in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell linesin vitro.In vivoinactivation ofABCA1or expression ofABCA1mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function ofABCA1. Mechanistically,ABCA1mutations impair the tumor-suppressor functions of WTABCA1in 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 inABCA1that 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.
