Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies

Hui Yang, Stefan Kurtenbach, Ying Guo, Ines Lohse, Michael A. Durante, Jianping Li, Zhaomin Li, Hassan Al-Ali, Lingxiao Li, Zizhen Chen, Matthew G. Field, Peng Zhang, Shi Chen, Shohei Yamamoto, Zhuo Li, Yuan Zhou, Stephen D Nimer, J. William Harbour, Claes R Wahlestedt, Mingjiang XuFeng-Chun Yang

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag- Asxl1Y588X transgenic mouse model, Asxl1Y588XTg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588XTg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit1 cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography–tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588XTg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies. (Blood. 2018;131(3):328-341)

Original languageEnglish (US)
Pages (from-to)328-341
Number of pages14
JournalBlood
Volume131
Issue number3
DOIs
StatePublished - Jan 18 2018

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Comb and Wattles
Stem cells
Chromatin
Mass spectrometry
Neoplasms
Screening
Hematopoietic Stem Cells
Bone
Proteins
Blood
Genes
Cells
RNA
Liquids
RNA Sequence Analysis
Hematopoietic System
Mutation
Preclinical Drug Evaluations
Pharmaceutical Preparations
Epigenomics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. / Yang, Hui; Kurtenbach, Stefan; Guo, Ying; Lohse, Ines; Durante, Michael A.; Li, Jianping; Li, Zhaomin; Al-Ali, Hassan; Li, Lingxiao; Chen, Zizhen; Field, Matthew G.; Zhang, Peng; Chen, Shi; Yamamoto, Shohei; Li, Zhuo; Zhou, Yuan; Nimer, Stephen D; William Harbour, J.; Wahlestedt, Claes R; Xu, Mingjiang; Yang, Feng-Chun.

In: Blood, Vol. 131, No. 3, 18.01.2018, p. 328-341.

Research output: Contribution to journalArticle

Yang, H, Kurtenbach, S, Guo, Y, Lohse, I, Durante, MA, Li, J, Li, Z, Al-Ali, H, Li, L, Chen, Z, Field, MG, Zhang, P, Chen, S, Yamamoto, S, Li, Z, Zhou, Y, Nimer, SD, William Harbour, J, Wahlestedt, CR, Xu, M & Yang, F-C 2018, 'Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies', Blood, vol. 131, no. 3, pp. 328-341. https://doi.org/10.1182/blood-2017-06-789669
Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J et al. Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood. 2018 Jan 18;131(3):328-341. https://doi.org/10.1182/blood-2017-06-789669
Yang, Hui ; Kurtenbach, Stefan ; Guo, Ying ; Lohse, Ines ; Durante, Michael A. ; Li, Jianping ; Li, Zhaomin ; Al-Ali, Hassan ; Li, Lingxiao ; Chen, Zizhen ; Field, Matthew G. ; Zhang, Peng ; Chen, Shi ; Yamamoto, Shohei ; Li, Zhuo ; Zhou, Yuan ; Nimer, Stephen D ; William Harbour, J. ; Wahlestedt, Claes R ; Xu, Mingjiang ; Yang, Feng-Chun. / Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. In: Blood. 2018 ; Vol. 131, No. 3. pp. 328-341.
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abstract = "Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag- Asxl1Y588X transgenic mouse model, Asxl1Y588XTg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588XTg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit1 cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography–tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588XTg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies. (Blood. 2018;131(3):328-341)",
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AU - Li, Jianping

AU - Li, Zhaomin

AU - Al-Ali, Hassan

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AU - Field, Matthew G.

AU - Zhang, Peng

AU - Chen, Shi

AU - Yamamoto, Shohei

AU - Li, Zhuo

AU - Zhou, Yuan

AU - Nimer, Stephen D

AU - William Harbour, J.

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