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

Omar Abdel-Wahab, Jie Gao, Mazhar Adli, Anwesha Dey, Thomas Trimarchi, Young Rock Chung, Cem Kuscu, Todd Hricik, Delphine Ndiaye-Lobry, Lindsay M. LaFave, Richard Koche, Alan H. Shih, Olga A. Guryanova, Eunhee Kim, Sheng Li, Suveg Pandey, Joseph Y. Shin, Leon Telis, Jinfeng Liu, Parva K. BhattSebastien Monette, Xinyang Zhao, Christopher E. Mason, Christopher Y. Park, Bradley E. Bernstein, Iannis Aifantis, Ross L. Levine

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2641-2659
Number of pages19
JournalJournal of Experimental Medicine
Volume210
Issue number12
DOIs
StatePublished - Nov 1 2013

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Myelodysplastic Syndromes
Comb and Wattles
Hematopoietic Stem Cells
Hematopoiesis
Knockout Mice
Anophthalmos
Null Lymphocytes
Microcephaly
Gene Knockout Techniques
Mutation
Cleft Palate
Genes
Transplantation
RNA
Phenotype
Neoplasms

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Abdel-Wahab, O., Gao, J., Adli, M., Dey, A., Trimarchi, T., Chung, Y. R., ... Levine, R. L. (2013). Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. Journal of Experimental Medicine, 210(12), 2641-2659. https://doi.org/10.1084/jem.20131141

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

In: Journal of Experimental Medicine, Vol. 210, No. 12, 01.11.2013, p. 2641-2659.

Research output: Contribution to journalArticle

Abdel-Wahab, O, Gao, J, Adli, M, Dey, A, Trimarchi, T, Chung, YR, Kuscu, C, Hricik, T, Ndiaye-Lobry, D, LaFave, LM, Koche, R, Shih, AH, Guryanova, OA, Kim, E, Li, S, Pandey, S, Shin, JY, Telis, L, Liu, J, Bhatt, PK, Monette, S, Zhao, X, Mason, CE, Park, CY, Bernstein, BE, Aifantis, I & Levine, RL 2013, 'Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo', Journal of Experimental Medicine, vol. 210, no. 12, pp. 2641-2659. https://doi.org/10.1084/jem.20131141
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. / Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 12. pp. 2641-2659.
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abstract = "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.",
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AU - Abdel-Wahab, Omar

AU - Gao, Jie

AU - Adli, Mazhar

AU - Dey, Anwesha

AU - Trimarchi, Thomas

AU - Chung, Young Rock

AU - Kuscu, Cem

AU - Hricik, Todd

AU - Ndiaye-Lobry, Delphine

AU - LaFave, Lindsay M.

AU - Koche, Richard

AU - Shih, Alan H.

AU - Guryanova, Olga A.

AU - Kim, Eunhee

AU - Li, Sheng

AU - Pandey, Suveg

AU - Shin, Joseph Y.

AU - Telis, Leon

AU - Liu, Jinfeng

AU - Bhatt, Parva K.

AU - Monette, Sebastien

AU - Zhao, Xinyang

AU - Mason, Christopher E.

AU - Park, Christopher Y.

AU - Bernstein, Bradley E.

AU - Aifantis, Iannis

AU - Levine, Ross L.

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N2 - 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.

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