A novel ASXL1–OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies

Inoue, Daichi; Fujino, Takeshi; Sheridan, Paul; Zhang, Yao-Zhong; Nagase, Reina; Horikawa, Sayuri; Li, Zaomin; Matsui, Hirotaka; Kanai, Akinori; Saika, Makoto; Yamaguchi, Rui; Kozuka‐Hata, Hiroko; Kawabata, Kimihito C.; Yokoyama, Akihiko; Goyama, Susumu; Inaba, Toshiya; Imoto, Seiya; Miyano, Satoru; Xu, Mingjiang; Yang, Feng Chun; Oyama, Masaaki; Kitamura, Toshio

doi:10.1038/s41375-018-0083-3

Cited by 57 publications

(60 citation statements)

References 54 publications

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“…By contrast, mutations involving NPM1 or signaling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis [113,114]. Novel promising therapeutic strategies had been established for targeting ASXL1 mutated myeloid malignancies by blocking interactions between ASXL1 and associating epigenetic regulators [115][116][117][118]. Furthermore, recurrent somatic mutations in more than 50 genes have been identified in 80-90% of MDS.…”

Section: Asxl1mentioning

confidence: 99%

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Zhang

et al. 2020

Exp Hematol Oncol

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Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy characterized by recurrent gene mutations. Genomic heterogeneity, patients' individual variability, and recurrent gene mutations are the major obstacles among many factors that impact treatment efficacy of the AML patients. With the application of cost-and time-effective next-generation sequencing (NGS) technologies, an enormous diversity of genetic mutations has been identified. The recurrent gene mutations and their important roles in acute myeloid leukemia (AML) pathogenesis have been studied extensively. In this review, we summarize the recent development on the gene mutation in patients with AML.

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Section: Asxl1mentioning

confidence: 99%

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Zhang

et al. 2020

Exp Hematol Oncol

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“…ASXL1 plays a key role in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies [22]. Also, ASXL1 mutations may affect epigenetic regulation by inhibiting ubiquitination of lysine 119 at histone H2A (H2AK119).…”

Section: Discussionmentioning

confidence: 99%

“…Tacrolimus and short-term methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. On the 18th day after transplantation, the patient received neutrophil engraftment followed by reticulocyte engraftment 14 days later and platelet engraftment 22 by RT-PCR (International Scale). Despite treatment, the patient died on the 121st day from GVHD and thrombotic microangiopathy, which developed after the patient presented with GVHD.…”

Section: Introductionmentioning

confidence: 99%

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation

et al. 2020

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Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22) (q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk.The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.

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“…However, whether hcfc1a regulates asxl1 by directly binding to the asxl1 promoter is still not known, but interestingly ASXL1 and HCFC1 interact with one another in myeloid cells to regulate proliferation and differentiation (58). Thus, these two proteins may regulate the activity of one another at multiple levels.…”

Section: Discussionmentioning

confidence: 99%

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain.

Castro

Reyes

Reyes-Nava

et al. 2020

Preprint

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Background: Precise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function. The HCFC1 gene encodes a transcriptional co-factor that regulates cell proliferation, and previous studies suggest that HCFC1 regulates NPC function. However, the molecular mechanism underlying these cellular deficits has not been completely characterized. Methods: Here we created a zebrafish harboring mutations in the hcfc1a gene (the hcfc1a co60/+ allele), one ortholog of HCFC1 and utilized immunohistochemistry and RNA-sequencing technology to understand the function of hcfc1a during neural development. Results: The hcfc1a co60/+ allele results in an increased number of NPCs, neurons, and radial glial cells. These deficits are associated with the abnormal expression of asxl1 , a polycomb transcription factor, which we identified as a downstream effector of hcfc1a using high throughput RNA sequencing technology. Inhibition of asxl1 activity and/or expression in larvae harboring the hcfc1a co60/+ allele completely restored the number of NPCs to normal levels. Conclusion: Collectively, our data demonstrate a novel pathway in which hcfc1a regulates NPCs and neurogenesis.

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A novel ASXL1–OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies

Cited by 57 publications

References 54 publications

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Clinical implications of recurrent gene mutations in acute myeloid leukemia

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain.

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