ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion

Madan, Vikas; Lin, Han; Hattori, Norimichi; Teoh, Weoi Woon; Mayakonda, Anand; Sun, Qiao-Yang; Ding, Ling-Wen; Nordin, Hazimah Binte Mohd; Lim, Su Lin; Pavithra, S.; Dakle, Pushkar; Sundaresan, Janani; Doan, Ngan; Sanada, Masashi; Sato‐Otsubo, Aiko; Meggendorfer, Manja; Yang, Henry; Said, Jonathan; Ogawa, Seishi; Haferlach, Torsten; Liang, Der‐Cherng; Shih, Lee‐Yung; Nakamaki, Tsuyoshi; Wang, Q. Tian; Koeffler, H. Phillip

doi:10.3324/haematol.2018.189928

Cited by 16 publications

(14 citation statements)

References 46 publications

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“…Our previous study reported DHX15 R222G mutation in a Chinese family with AML and some sporadic AML patients 4 . The same mutation has been reported in AML patients by other groups 5‐10 . Our study found DHX15 is upregulated and associated with poor outcomes, which indicates the importance of DHX15 and DHX15 R222G in AML pathogenesis.…”

Section: Introductionsupporting

confidence: 84%

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

et al. 2021

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Gene alterations are recognized as important events in acute myeloid leukemia (AML) progression. Studies on hematopoiesis of altered genes contribute to a better understanding on their roles in AML progression. Our previous work reported a DEAH box helicase 15 (DHX15) R222G mutation in AML patients, and we showed DHX15 overexpression is associated with poor prognosis in AML patients. In this work, we further study the role of dhx15 in zebrafish developmental hematopoiesis by generating dhx15−/− zebrafish using transcription activator‐like effector nuclease technology. Whole‐mount in situ hybridization (WISH) analysis showed hematopoietic stem/progenitor cells were dramatically perturbed when dhx15 was deleted. Immunofluorescence staining indicated inhibited hematopoietic stem/progenitor cell (HSPC) proliferation instead of accelerated apoptosis were detected in dhx15−/− zebrafish. Furthermore, our data showed that HSPC defect is mediated through the unfolded protein response (UPR) pathway. DHX15 R222G mutation, a recurrent mutation identified in AML patients, displayed a compromised function in restoring HSPC failure in dhx15−/−; Tg (hsp: DHX15 R222G) zebrafish. Collectively, this work revealed a vital role of dhx15 in the maintenance of definitive hematopoiesis in zebrafish through the unfolded protein respone pathway. The study of DHX15 and DHX15 R222G mutation could hold clinical significance for evaluating prognosis of AML patients with aberrant DHX15 expression.

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Section: Introductionsupporting

confidence: 84%

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

et al. 2021

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“…After induction II, there was no significant difference in the average VAF for the 2 groups. We also examined the clearance of nonrandom AML-associated mutations [29][30][31]51 by treatment regimen and by using a criterion of VAF ,1%. 30 The VAFs of all genes selected were ,1% after the second induction course, irrespective of the treatment arm.…”

Section: Discussionmentioning

confidence: 99%

Minimally myelosuppressive regimen for remission induction in pediatric AML: long-term results of an observational study

Chen

Gao

et al. 2021

Blood Advances

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Treatment refusal and death as a result of toxicity account for most treatment failures among children with acute myeloid leukemia (AML) in resource-constrained settings. We recently reported the results of treating children with AML with a combination of low-dose cytarabine and mitoxantrone or omacetaxine mepesuccinate with concurrent granulocyte colony-stimulating factor (G-CSF) (low-dose chemotherapy [LDC]) for remission induction followed by standard postremission strategies. We have now expanded the initial cohort and have provided long-term follow-up. Eighty-three patients with AML were treated with the LDC regimen. During the study period, another 100 children with AML received a standard-dose chemotherapy (SDC) regimen. Complete remission was attained in 88.8% and 86.4% of patients after induction in the LDC and SDC groups, respectively (P = .436). Twenty-two patients in the LDC group received SDC for the second induction course. Significantly more high-risk AML patients were treated with the SDC regimen (P = .035). There were no significant differences between the LDC and SDC groups in 5-year event-free survival (61.4% ± 8.7% vs 65.2% ± 7.4%, respectively; P = .462), overall survival (72.7% ± 6.9% vs 72.5% ± 6.2%, respectively; P = .933), and incidence of relapse (20.5% ± 4.5% vs 17.6% ± 3.9%, respectively; P = .484). Clearance of mutations based on the average variant allele frequency at complete remission in the LDC and SDC groups was 1.9% vs 0.6% (P < .001) after induction I and 0.17% vs 0.078% (P = .052) after induction II. In conclusion, our study corroborated the high remission rate reported for children with AML who received at least 1 course of LDC. The results, although preliminary, also suggest that long-term survival of these children is comparable to that of children who receive SDC regimens.

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“…Asxl2 encodes a member of a family of epigenetic regulators involved in the assembly of transcription factors at specific genomic loci. A previous study indicated that Asxl2 was necessary for maintaining steady-state hematopoiesis ( 41 ). ASXL2 interacts with peroxisome proliferator-activated receptor (PPAR)γ and PPAR-activated receptor during adipogenesis ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Role of Asxl2 in non‑alcoholic steatohepatitis‑related hepatocellular carcinoma developed from diabetes

Zhang

Teng

et al. 2020

Int J Mol Med

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The present study investigated the mechanism(s) of non-alcoholic steatohepatitis-related hepatocellular carcinoma (NASH-HCC) developed from diabetes. Streptozotocin and a high-fat diet (STZ-HFD) were used to induce NASH-HCC in ApoE −/− mice. Mouse liver functions were evaluated by H&E staining, liver/body weight and serum biochemical analysis. The expression levels of inflammation-associated factors were determined by RT-qPCR. Gene expression profiles related to molecular functions and pathways of NASH-HCC were examined by principal component analysis, heatmap, gene ontology and KEGG pathway enrichment analysis. Differentially expressed genes (DEGs) in tumor tissues were confirmed by RT-qPCR. The expression of Asxl2 in human NASH-HCC, other HCC tissues and HCC cells was measured by western blot (WB analysis) and RT-qPCR. For SNU-182 cells transfected with siAsxl2 or Hep3B cells with Asxl2 overexpression, cell proliferation, cell cycle, migration and invasion were respectively determined by CCK-8 assays, flow cytometry, wounding healing and Transwell assays. The expression levels of cell metastasis- and cycle-related proteins were determined by WB analysis and RT-qPCR. NASH-HCC model mice exhibited tumor protrusion with severe steatosis. The blood glucose concentration, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and low-density lipoprotein (LDL), total bile acid (TBA) and the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, glypican 3 (GPC3) and transforming growth factor (TGF)-β were all increased in NASH-HCC model mice. DEGs were mainly related to chromosome organization, the cell cycle and the mitogen-activated kinase (MAPK) pathway. Asxl2 was significantly downregulated in HCC tissues and cells, and this regulated cell growth, migration and invasion. The gene expression pattern, related molecular functions and signaling pathways of NASH-HCC differed from those of normal liver tissues. Additionally, the downregulation of Asxl2 may play a potential role in development of NASH-HCC in patients with diabetes.

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ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion

Cited by 16 publications

References 46 publications

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

Minimally myelosuppressive regimen for remission induction in pediatric AML: long-term results of an observational study

Role of Asxl2 in non‑alcoholic steatohepatitis‑related hepatocellular carcinoma developed from diabetes

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