Loss of Asxl2 leads to myeloid malignancies in mice

Li, Jianping; He, Fuhong; Zhang, Peng; Chen, Shi; Shi, Hui; Sun, Yanling; Guo, Ying; Yang, Hui; Man, Na; Greenblatt, Sarah; Li, Zhaomin; Guo, Zhengyu; Zhou, Yuan; Wang, Lan; Morey, Lluís; Williams, Siôn L.; Chen, Xi; Wang, Qun Tian; Nimer, Stephen D.; Yu, Peng; Wang, Qian Fei; Xu, Mingjiang; Yang, Feng Chun

doi:10.1038/ncomms15456

Cited by 26 publications

(32 citation statements)

References 42 publications

(64 reference statements)

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“…Single-cell suspensions from BM and PB were stained with panels of fluorochrome-conjugated antibodies (Supplemental Table 9). Flow cytometric analysis of HSCs/ HPCs was performed as previously described (26). The analyses were performed using a BD FACSCanto II or LSR Fortessa flow cytometer (BD Biosciences).…”

Section: Discussionmentioning

confidence: 99%

“…ChIP-Seq and data analysis. ChIP assays were performed using cKit + cells from 8-month-old Asxl1 +/-Nf1 +/and WT mice as previously reported (26). Genomic DNA regions of interest were isolated using antibodies against H3K4me3 (C15410003, Diagenode), H3K4me1 (C15410194, Diagenode), H3K27ac (C15410196, Diagenode), and H3K27me3 (07-449, MilliporeSigma).…”

Section: Methodsmentioning

confidence: 99%

“…libraries were prepared using the MicroPlex Library Preparation Kit (Diagenode) and sequenced with a read length of 76 bp on an Illumina NextSeq 500 system. Approximately 20 to 50 million single-end reads per sample were aligned to the mouse genome (GRCm38/mm10), and enrichment peaks of histone modifications were called as described previously (26). Using MULTOVL version 1.2 (71), with the parameters '-u -m 1', a total of 31277, 35312, 87995, and 37637 peak regions were present in at least 1 biological replicate of H3K4me3, H3K27me3, H3K4me1, and H3K27ac ChIP-Seqs, respectively (the union of overlapping regions was reported; minimum overlap required 1 bp).…”

Section: Author Contributionsmentioning

confidence: 99%

“…Using MULTOVL version 1.2 (71), with the parameters '-u -m 1', a total of 31277, 35312, 87995, and 37637 peak regions were present in at least 1 biological replicate of H3K4me3, H3K27me3, H3K4me1, and H3K27ac ChIP-Seqs, respectively (the union of overlapping regions was reported; minimum overlap required 1 bp). A total of 109,419 union regions of 4 histone modifications were assigned to the nearest genes within 100 kb using RefSeq annotation (released June 28, 2017) from UCSC as described previously (26). Read counting and differential enrichment analysis for each histone modification were done with CisGenome (72) and edgeR (70), respectively.…”

Section: Author Contributionsmentioning

confidence: 99%

“…Although we observed a steady decline of replating potential in WT cultures, we detected significantly higher replating activity over 4 successive replating periods in Asxl1 +/-Nf1 +/-CD34 − LSK cell cultures ( Figure 2F), suggesting an increased selfrenewal capacity of Asxl1 +/-Nf1 +/-CD34 -LSK cells. To further determine whether haploinsufficient loss of Asxl1 and Nf1 affects HSC/ HPC symmetric/asymmetric cell division, we next performed paired daughter cell assays (26) to assess the proportions of symmetric self-renewal, symmetric differentiation, and asymmetric division using sorted CD34 − LSK cell populations from mice of the 4 genotypes. Haploinsufficiency of Asxl1 and Nf1 resulted in a higher proportion of cells with symmetric self-renewal capacity (43.1%) compared with WT cells (27.7%) ( Figure 2G).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang¹,

He²,

Bai³

et al. 2018

Journal of Clinical Investigation

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Author Contributionsmentioning

confidence: 99%

Section: Author Contributionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Zhang¹,

He²,

Bai³

et al. 2018

Journal of Clinical Investigation

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Understanding the phenotypic spectrum of ASXL‐related disease: Ten cases and a review of the literature

Cuddapah

Dubbs

Adang

et al. 2021

American J of Med Genetics Pt A

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Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring–Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi–Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge–Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL‐related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

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Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

Yang,

Wei,

Gong

2023

Cancer Medicine

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ObjectiveThe objective of the study was to determine the prognosis and risk factors for additional sex combs like 1 (ASXL1) mutations in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).Population and MethodsThis retrospective study enrolled 219 adult patients with newly diagnosed AML and MDS, who were treated in West China Hospital from October 2018 to January 2022. The primary clinical outcome was evaluated by overall survival (OS) followed up to January 2023. Kaplan–Meier analysis and Cox multivariate regression analysis were performed to identify potential prognostic parameters in patients with ASXL1 mutations (mt).ResultsA total of 34 (15.53%) ASXL1mt were detected, which occurred more frequently in the elderly and MDS cohorts (p < 0.001). Significantly lower blasts% (p < 0.001) and higher frequencies of mutant RUNX1, SRSF2, STAG2, EZH2, and SETBP1 (p < 0.02) were observed in the ASXL1mt cohort. Patients with ASXL1mt manifested with a worse complete remission rate (p = 0.011), and an inferior OS was shown in subgroups with MDS, co‐mutations of RUNX1, SRSF2, or NRAS, as well as mutations in G646W (p < 0.05). Multivariate analysis considering age, diagnosis, co‐mutations, and mutation site confirmed an independently adverse prognosis of mutations in G646W (HR = 4.302, 95% CI: 1.150–16.097) or RUNX1 co‐mutations (HR = 4.620, 95% CI: 1.385–15.414) in the ASXL1mt cohort.ConclusionOur study indicated that mutations in G646W or RUNX1 co‐mutations are closely associated with a dismal clinical outcome in patients with AML and MDS harboring ASXL1mt. Considering the poor prognosis and risk factors in patients with ASXL1mt, more available treatments should be pursued.

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Loss of Asxl2 leads to myeloid malignancies in mice

Cited by 26 publications

References 42 publications

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

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

Understanding the phenotypic spectrum of ASXL‐related disease: Ten cases and a review of the literature

Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

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