ABCA1 exerts tumor-suppressor function in myeloproliferative neoplasms Journal Article

   


Authors: Viaud, M.; Abdel-Wahab, O.; Gall, J.; Ivanov, S.; Guinamard, R.; Sore, S.; Merlin, J.; Ayrault, M.; Guilbaud, E.; Jacquel, A.; Auberger, P.; Wang, N.; Levine, R. L.; Tall, A. R.; Yvan-Charvet, L.
Article Title: ABCA1 exerts tumor-suppressor function in myeloproliferative neoplasms
Abstract: 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. © 2020 The Author(s) 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. © 2020 The Author(s)
Keywords: signal transduction; clinical article; controlled study; chronic myelomonocytic leukemia; gene mutation; human cell; janus kinase 2; histopathology; cancer growth; nonhuman; flow cytometry; genetic analysis; animal cell; mouse; gene overexpression; gene expression; animal experiment; animal model; gene function; in vivo study; in vitro study; cancer inhibition; genetic transfection; cell culture; gene identification; western blotting; hematopoietic cell; hematopoiesis; gene inactivation; leukocyte count; nuclear reprogramming; antiproliferative activity; somatic mutations; high density lipoprotein; apolipoprotein a1; high throughput sequencing; mapk signaling; abc transporter a1; human; male; priority journal; article; hek293 cell line; hematopoietic stem and progenitor cells; cholesterol efflux; leukemia biology; atp-binding cassette transporter; ten-eleven translocation 2; cd131 antigen; abca1 gene; monocytic leukemia cell line
Journal Title: Cell Reports
Volume: 30
Issue: 10
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2020-03-10
Start Page: 3397
End Page: 3410.e5
Language: English
DOI: 10.1016/j.celrep.2020.02.056
PUBMED: 32160545
PROVIDER: scopus
PMCID: PMC7473128
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081000291&doi=10.1016%2fj.celrep.2020.02.056&partnerID=40&md5=9162034e1de8c634f30c77e5bbe35e2d
Notes: Article -- Source: Scopus
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MSK Authors
  1. Ross Levine
    775 Levine
  2. Omar Ibrahim Abdel-Wahab
    573 Abdel-Wahab
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