Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo

• Published in: The Journal of experimental medicine 2013-11, Vol.210 (12), p.2641-2659
• Main Authors: Abdel-Wahab, Omar, Gao, Jie, Adli, Mazhar, Dey, Anwesha, Trimarchi, Thomas, Chung, Young Rock, Kuscu, Cem, Hricik, Todd, Ndiaye-Lobry, Delphine, Lafave, Lindsay M, Koche, Richard, Shih, Alan H, Guryanova, Olga A, Kim, Eunhee, Li, Sheng, Pandey, Suveg, Shin, Joseph Y, Telis, Leon, Liu, Jinfeng, Bhatt, Parva K, Monette, Sebastien, Zhao, Xinyang, Mason, Christopher E, Park, Christopher Y, Bernstein, Bradley E, Aifantis, Iannis, Levine, Ross L
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - etiology; Abnormalities, Multiple - genetics; Animals; Dioxygenases; Disease Models, Animal; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Epigenesis, Genetic; Female; Gene Deletion; Germ-Line Mutation; Hematopoiesis - genetics; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myelodysplastic Syndromes - etiology; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Phenotype; Pregnancy; Protein Binding; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Repressor Proteins - deficiency; Repressor Proteins - genetics; Repressor Proteins - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20131141

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.