ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.
Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.
Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Omar
O
Abdel-Wahab
Mazhar
M
Adli
Lindsay M
LM
LaFave
Jie
J
Gao
Todd
T
Hricik
Alan H
AH
Shih
Suveg
S
Pandey
Jay P
JP
Patel
Young Rock
YR
Chung
Richard
R
Koche
Fabiana
F
Perna
Xinyang
X
Zhao
Jordan E
JE
Taylor
Christopher Y
CY
Park
Martin
M
Carroll
Ari
A
Melnick
Stephen D
SD
Nimer
Jacob D
JD
Jaffe
Iannis
I
Aifantis
Bradley E
BE
Bernstein
Ross L
RL
Levine
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006413:Hematopoietic System / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008745:Methylation; D051379:Mice; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
C473949:ASXL1 protein, human; C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C088144:HoxA protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D043222:Ubiquitin Thiolesterase; D018631:ras Proteins