ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

被引：57

作者：

Micol, Jean-Baptiste ^{[1
,2
,3
,4
]}

Pastore, Alessandro ^{[3
,4
]}

Inoue, Daichi ^{[3
,4
]}

Duployez, Nicolas ^{[5
]}

Kim, Eunhee ^{[6
]}

Lee, Stanley Chun-Wei ^{[3
,4
]}

Durham, Benjamin H. ^{[3
,4
]}

Chung, Young Rock ^{[3
,4
]}

Cho, Hana ^{[3
,4
]}

Zhang, Xiao Jing ^{[3
,4
]}

Yoshimi, Akihide ^{[3
,4
]}

Krivtsov, Andrei ^{[7
,8
]}

Koche, Richard ^{[9
]}

Solary, Eric ^{[1
,2
]}

Sinha, Amit ^{[10
]}

Preudhomme, Claude ^{[5
]}

Abdel-Wahab, Omar ^{[3
,4
,11
]}

机构：

[1] INSERM, UMR1170, Hematol Dept, Gustave Roussy Canc Campus Grand Paris, F-94800 Villejuif, France

[2] Univ Paris Sud, Fac Med, F-94270 Paris, France

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[4] Weill Cornell Med Coll, New York, NY 10065 USA

[5] Univ Lille Nord France, CHRU Lille, INSERM,Canc Res Inst Lille, Lab Hematol & Tumor Bank,UMR S 1172, F-59037 Lille, France

[6] Ulsan Natl Inst Sci & Technol, Sch Life Sci, Ulsan 44919, South Korea

[7] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA

[8] Harvard Med Sch, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA 02215 USA

[9] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[10] Basepair Inc, New York, NY 10011 USA

[11] Mem Sloan Kettering Canc Ctr, Leukemia Serv, Dept Med, New York, NY 10065 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

日本学术振兴会;

关键词：

ACUTE MYELOID-LEUKEMIA; ADDITIONAL-SEX-COMBS; ACUTE MYELOGENOUS LEUKEMIA; STEM-CELL FUNCTION; EXTRAMEDULLARY LEUKEMIA; CLONAL HEMATOPOIESIS; SOMATIC MUTATIONS; MURINE HOMOLOG; T(8/21) AML; GENE;

D O I：

10.1038/ncomms15429

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

引用

页数：13

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