Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.
Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.
复制标题
DOI：
10.1038/s41467-018-05085-9
复制
发表时间：
2018-07-16
影响因子：
16.6
通讯作者：
Kitamura T
中科院分区：
文献类型：
--
作者：
Asada S;Goyama S;Inoue D;Shikata S;Takeda R;Fukushima T;Yonezawa T;Fujino T;Hayashi Y;Kawabata KC;Fukuyama T;Tanaka Y;Yokoyama A;Yamazaki S;Kozuka-Hata H;Oyama M;Kojima S;Kawazu M;Mano H;Kitamura T
ASXL1突变常见于髓系肿瘤，且与预后不良有关。然而，突变ASXL1诱导白血病发生的机制尚不清楚。在这项研究中，我们报道了c端截断形式的突变体ASXL1 （ASXL1- mt）和BAP1在促进髓系白血病发生中的相互增强作用。BAP1的表达导致ASXL1-MT单泛素化增加，这反过来又增加了BAP1的催化功能。这种过度活跃的ASXL1-MT/BAP1复合体促进造血祖细胞的异常髓系分化，并加速runx1 - eto驱动的白血病发生。从机制上讲，该复合物通过去除H2AK119泛素化诱导后HOXA基因和IRF8的上调。重要的是，BAP1缺失抑制了表达asxl1 - mt的髓系白血病细胞的后端HOXA基因表达和白血病发生。此外，BAP1也是后端HOXA基因失调的mll融合白血病细胞生长所必需的。这些数据表明，长期以来被认为是肿瘤抑制因子的BAP1实际上在髓系肿瘤中起促瘤作用。ASXL1基因常在髓系恶性肿瘤中发生突变。在这里，作者表明突变体ASXL1和BAP1处于一个正反馈回路中，BAP1诱导突变体ASXL1的单泛素化，这反过来增强BAP1的活性，从而通过HOXA簇和IRF8增强髓细胞转化。
ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms. ASXL1 gene is often mutated in myeloid malignancies. Here, the authors show that mutant ASXL1 and BAP1 are in a positive feedback loop such that BAP1 induces monoubiquitination of mutant ASXL1, which in turn enhances BAP1 activity to potentiate myeloid transformation via HOXA clusters and IRF8.
登录
查看更多内容
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
20.3
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
影响因子：
11.4
作者：
Feinberg, Mark W.;Wara, Akm Khyrul;Jain, Mukesh K.
通讯作者：
Jain, Mukesh K.