Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.
Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10-30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.
Human Oncology and Pathogenesis Program, 2 Leukemia Service, 3 Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, and 4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
Omar
O
Abdel-Wahab
Jie
J
Gao
Mazhar
M
Adli
Anwesha
A
Dey
Thomas
T
Trimarchi
Young Rock
YR
Chung
Cem
C
Kuscu
Todd
T
Hricik
Delphine
D
Ndiaye-Lobry
Lindsay M
LM
Lafave
Richard
R
Koche
Alan H
AH
Shih
Olga A
OA
Guryanova
Eunhee
E
Kim
Sheng
S
Li
Suveg
S
Pandey
Joseph Y
JY
Shin
Leon
L
Telis
Jinfeng
J
Liu
Parva K
PK
Bhatt
Sebastien
S
Monette
Xinyang
X
Zhao
Christopher E
CE
Mason
Christopher Y
CY
Park
Bradley E
BE
Bernstein
Iannis
I
Aifantis
Ross L
RL
Levine
D000015:Abnormalities, Multiple / Q000209:etiology* / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D049308:Dioxygenases; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011247:Pregnancy; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
C473949:ASXL1 protein, human; C510915:Asxl1 protein, mouse; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse