Other
20 Authors
- Yang H,
- Harbour JW,
- Durante MA,
- Chen S,
- Yang FC,
- Lohse I,
- Zhang P,
- Xu M,
- Li Z,
- Li L,
- Kurtenbach S,
- Yamamoto S,
- Chen Z,
- Guo Y,
- Zhou Y,
- Field MG,
- Li J,
- Al-Ali H,
- Nimer SD,
- Wahlestedt C
| First Author | Yang H | Year | 2018 |
| Journal | Blood | Volume | 131 |
| Issue | 3 | Pages | 328-341 |
| PubMed ID | 29113963 | Mgi Jnum | J:257690 |
| Mgi Id | MGI:6120027 | Doi | 10.1182/blood-2017-06-789669 |
| Citation | Yang H, et al. (2018) Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood 131(3):328-341 |
| abstractText | Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1(Y588X) transgenic mouse model, Asxl1(Y588X) Tg, to express a truncated FLAG-ASXL1(aa1-587) protein in the hematopoietic system. The Asxl1(Y588X) Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1(aa1-587) truncating protein expression results in more open chromatin in cKit(+) cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1(aa1-587) acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1(Y588X) Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1(aa1-587) plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies. |
