The role of ASXL1 in hematopoiesis and myeloid malignancies

Asada, Shuhei; Fujino, Takeshi; Goyama, Susumu; Kitamura, Toshio

doi:10.1007/s00018-019-03084-7

Cited by 99 publications

(82 citation statements)

References 119 publications

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“…The results demonstrated the different gene mutation patterns between the AML patients and MDS patients. Other groups support our finding of similar gene mutation patterns and mutation frequencies between MDS and AML patients [48].…”

Section: Discussionsupporting

confidence: 89%

Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia

et al. 2020

Exp Hematol Oncol

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Background: In this study, we retrospectively summarized the differences of molecular gene mutations between MDS and AML patients, as well as the young and older age groups of MDS and AML patients. We also analyzed the response of newly diagnosed AML patients to standard DA or IA induction chemotherapy and the relationship between the chemotherapy outcome and the frequency of different gene mutation abnormalities. Methods: NGS assay covering 43 genes was studied in 93 de novo MDS and 325 non-M3 AML patients. Bone marrow samples from all patients underwent gene mutational analysis by NGS. Results: At least one non-synonymous gene mutation was detected in 279 AML patients (85.8%) and 85 MDS patients (91.4%). Contrary to 59 years and younger AML patients, there was a significantly higher incidence of gene mutation in 60 years and older AML patients (2.37 vs 1.94, p = 0.034). Gene mutation incidence in 60 years and older MDS patients increased, but no statistical significance was present (1.95 vs 1.64, p = 0.216). AML patients had a significantly higher gene mutation incidence compared with MDS-MLD patients (2.02 vs 1.63, p = 0.046). Gene mutation incidence was higher in patients with MDS-EB1/EB2 compared with patients with MDS-MLD but there was no statistical significance present (2.14 vs 1.63, p = 0.081). AML patients had significantly higher incidences of CEBPA, FLT3-ITD, DNMT3A, NPM1 and IDH1/2 gene mutations (p = 0.0043, 0.000, 0.030962, 0.002752, and 0.000628, respectively) and a lower incidence of TET2 and U2AF1 gene mutations (p = 0.000004 and 0.000, respectively) compared with MDS patients. Among the individual genes in different age groups, there were significantly higher incidences of RUNX1, IDH2, TP53 and SF3B1 gene mutations (p = 0.0478, 0.0028, 0.0024 and 0.005, respectively) as well as a trend of higher ASXL gene mutation (p = 0.057) in 60 years and older AML patients compared to 59 years and younger patients. There was no statistically significant difference in MDS patients with the different age groups and among the individual genes. Between AML patients and MDS patients among the different gene functional groups, AML patients had a significantly higher incidence of transcriptional deregulation (27.4% vs 15.1%, p = 0.014963), activated signalling (36.3% vs 10.8%, p = 0.000002) related gene mutations as well as a significantly lower incidence of RNA spliceosome (6.15% vs 60.1%, p = 0.000) related gene mutations. Furthermore, among the patients who received either IA or DA regimen

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Section: Discussionsupporting

confidence: 89%

Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia

et al. 2020

Exp Hematol Oncol

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“…Of the five members that were overexpressed (Table 4), BMI1 and EZH2 upregulation is correlated with poor prognosis in AML [41,42,43,44]. EZH2 and ASXL1 are frequently mutated in AML; these mutations are linked with poor prognosis [45], but the frequencies of these mutations did not differ between TLR responders and non-responders (Table S4).…”

Section: Discussionmentioning

confidence: 99%

Functional Toll-Like Receptors (TLRs) Are Expressed by a Majority of Primary Human Acute Myeloid Leukemia Cells and Inducibility of the TLR Signaling Pathway Is Associated with a More Favorable Phenotype

Brenner

Bruserud

2019

Cancers

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Acute myeloid leukemia (AML) is a highly heterogeneous disease with regard to biological characteristics and receptor expression. Toll-like receptors (TLRs) are upstream to the transcription factor NFκB and part of the innate immune system. They are differentially expressed on AML blasts, and during normal hematopoiesis they initiate myeloid differentiation. In this study, we investigated the response upon TLR stimulation in an AML cohort (n = 83) by measuring the increase of NFκB-mediated cytokine secretion. We observed that TLR4 is readily induced in most patients, while TLR1/2 response was more restricted. General response to TLR stimulation correlated with presence of nucleophosmin gene mutations, increased mRNA expression of proteins, which are part of the TLR signaling pathway and reduced expression of transcription-related proteins. Furthermore, signaling via TLR1/2 appeared to be linked with prolonged patient survival. In conclusion, response upon TLR stimulation, and especially TLR1/2 induction, seems to be part of a more favorable phenotype, which also is characterized by higher basal cytokine secretion and a more mature blast population.

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“…In CMML patients, additional TET2 mutations were associated with shorter survival in the presence of ASXL1 mutations (Cui et al, 2015(Cui et al, , 2016. In contrast, ASXL1 mutations are mutually exclusive with DNMT3A, NPM1, and SF3B1 mutations (Asada et al, 2019). These correlations should be taken into account for clinical prognosis as well as functional studies.…”

Section: Asxl1 Mutations In Myeloid Malignancies: Loss or Gain-of-funmentioning

confidence: 98%

The Functions and Mechanisms of PR-DUB in Malignancy

Cao

2021

Front. Mol. Biosci.

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The interplay between cancer genome and deregulated epigenomic control is critical for cancer initiation and progression. ASXL1 (Additional Sex combs-like 1) is frequently mutated in tumors especially myeloid malignancies. However, there remains a debate whether the mutations are loss or gain-of-function. Mechanistically, ASXL1 forms a complex with BAP1 for the erasure of mono-ubiquitylation at lysine 119 on Histone H2A (H2AK119ub1), a well-known histone mark associated with transcription repression. Unexpectedly, this de-ubiquitylation complex has been genetically defined as a Polycomb Repressive complex though the regulatory mechanisms are elusive. In this review, we will discuss about the functions of ASXL1 in malignancies and reconcile seemingly paradoxical effects of ASXL1 or BAP1 loss on transcription regulation.

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The role of ASXL1 in hematopoiesis and myeloid malignancies

Cited by 99 publications

References 119 publications

Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia

Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia

Functional Toll-Like Receptors (TLRs) Are Expressed by a Majority of Primary Human Acute Myeloid Leukemia Cells and Inducibility of the TLR Signaling Pathway Is Associated with a More Favorable Phenotype

The Functions and Mechanisms of PR-DUB in Malignancy

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