Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy

Peng Zhang, Fuhong He, Jie Bai, Shohei Yamamoto, Shi Chen, Lin Zhang, Mengyao Sheng, Lei Zhang, Ying Guo, Na Man, Hui Yang, Suyun Wang, Tao Cheng, Stephen D Nimer, Yuan Zhou, Mingjiang Xu, Qian Fei Wang, Feng-Chun Yang

Research output: Contribution to journalArticle

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Abstract

ASXL1 is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Here, we report that Asxl1 loss cooperated with haploinsufficiency of Nf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression in Asxl1Δ/Δ Nf1Δ/Δ mice. Concomitant mutations of ASXL1 and RAS pathway genes were associated with aggressive progression of myeloid malignancies in patients. This study sheds light on the effect of cooperation between epigenetic alterations and signaling pathways on accelerating the progression of myeloid malignancies and provides a rational therapeutic strategy for the treatment of myeloid malignancies with ASXL1 and RAS pathway gene mutations.

Original languageEnglish (US)
Pages (from-to)5383-5398
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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Haploinsufficiency
Chromatin
Mutation
Hematopoietic Stem Cells
Genes
Neoplasms
Myeloid Leukemia
Genetic Promoter Regions
Epigenomics
Transcriptional Activation
Disease Progression
Leukemia
Pharmacology
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy. / Zhang, Peng; He, Fuhong; Bai, Jie; Yamamoto, Shohei; Chen, Shi; Zhang, Lin; Sheng, Mengyao; Zhang, Lei; Guo, Ying; Man, Na; Yang, Hui; Wang, Suyun; Cheng, Tao; Nimer, Stephen D; Zhou, Yuan; Xu, Mingjiang; Wang, Qian Fei; Yang, Feng-Chun.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5383-5398.

Research output: Contribution to journalArticle

Zhang, P, He, F, Bai, J, Yamamoto, S, Chen, S, Zhang, L, Sheng, M, Zhang, L, Guo, Y, Man, N, Yang, H, Wang, S, Cheng, T, Nimer, SD, Zhou, Y, Xu, M, Wang, QF & Yang, F-C 2018, 'Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5383-5398. https://doi.org/10.1172/JCI121366
Zhang, Peng ; He, Fuhong ; Bai, Jie ; Yamamoto, Shohei ; Chen, Shi ; Zhang, Lin ; Sheng, Mengyao ; Zhang, Lei ; Guo, Ying ; Man, Na ; Yang, Hui ; Wang, Suyun ; Cheng, Tao ; Nimer, Stephen D ; Zhou, Yuan ; Xu, Mingjiang ; Wang, Qian Fei ; Yang, Feng-Chun. / Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5383-5398.
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AU - Cheng, Tao

AU - Nimer, Stephen D

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