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Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy
Peng Zhang, … , Qian-Fei Wang, Feng-Chun Yang
Peng Zhang, … , Qian-Fei Wang, Feng-Chun Yang
Published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5383-5398. https://doi.org/10.1172/JCI121366.
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Research Article Hematology Stem cells

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

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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.

Authors

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

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Figure 3

Cooperative effect of Asxl1 and Nf1 loss on the induction of a MYC-driven transcription signature.

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Cooperative effect of Asxl1 and Nf1 loss on the induction of a MYC-drive...
(A) Heatmap shows a unique expression signature in Asxl1+/– Nf1+/– cKit+ cells compared with that of control cells. Averaged expression values of DEGs (FC ≥1.2 and FDR <0.25) in 2 mice of each genotype were normalized and are shown. (B) Scatter plot displaying the number of regulated genes and targeted regulators for master regulators. Red and blue indicate up- and downregulated master regulators, respectively. (C) GSEA of the RNA-Seq data for Asxl1+/– Nf1+/– cKit+ cells compared with control cells. Selected dysregulated signatures are indicated in color and shown with the NES, P, and FDR values. (D) RT-qPCR verified the increase in mRNA levels of the indicated genes associated with NRAS, MYC, NUP98-HOXA9, and AML (n = 3–8 mice per group). Data represent the mean ± SEM. **P < 0.01, by 1-way ANOVA with Tukey’s multiple comparisons test. (E) Numbers and overlap of DEGs in Asxl1+/– Nf1+/– and single mutant cells. The significance of the overlaps was tested using GeneOverlap (a Fisher’s exact test–based method). (F) Heatmap displays the expression difference of selected dysregulated signatures from C in Asxl1+/– Nf1+/– and single mutant cells compared with controls (P < 0.05 and FDR <0.25).
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