Prognostic significance of <i>ASXL1</i> mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: A meta-analysis

Lin, Yun; Zheng, Yanfang; Wang, Zechuan; Wang, Shaoyuan

doi:10.1080/10245332.2015.1106815

Cited by 26 publications

(31 citation statements)

References 44 publications

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“…has also previously demonstrated that there were no significant correlations between SETBP1 mutations and age, and gender in CMML patients [ 11 ]. Our results show that the prognostic impact of SETBP1 mutations is similar to that of ASXL1 mutations, which is one of the strongest independent negative prognostic factor [ 13 , 20 ] in MDS and CMML patients (HR = 1.45, 95% CI (1.24–1.70)) [ 21 ].…”

Section: Discussionmentioning

confidence: 82%

Prognostic significance of SETBP1 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia: A meta-analysis

et al. 2017

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ObjectivesThis meta-analysis investigates the prognostic effect of SET binding protein 1 (SETBP1) mutations in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or chronic neutrophilic leukemia (CNL).MethodsEligible studies from Pubmed, Embase, and Web of Science were searched from database inception through April 2016. Hazard ratios (HRs) and 95% confidence interval (CI) of overall survival (OS) were pooled to calculate the prognostic significance of SETBP1 mutation in patients.ResultsA total of 12 studies with 2321 patients were included in this meta-analysis; 4 studies for MDS, 5 studies for CMML, and 3 studies for CNL. Pooled results suggested that MDS and CMML patients with SETBP1 mutations had a significantly poorer prognosis when compared with patients with wild-type SETBP1 (MDS: HR = 1.808, 95% CI (1.218–2.685), P = 0.001; CMML: HR = 2.223, 95% CI (1.493–3.308), P<0.001). SETBP1 mutations in CNL patients however, showed no significant effect on the overall survival (HR = 1.773, 95% CI (0.877–3.582), P = 0.111). The Begg’s and Egger’s tests did not show significant publication bias in any groups.ConclusionsCurrent evidence shows that SETBP1 mutation is associated with a poor prognosis in patients with MDS and CMML, but not in patients with CNL.

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Section: Discussionmentioning

confidence: 82%

Prognostic significance of SETBP1 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia: A meta-analysis

et al. 2017

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“…Mutations of ASXL1 have been reported in various types of leukemia 7, 8 . Although ASXL1 is considered to be a tumor suppressor, the molecular mechanism underlying tumor suppression is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…These findings add complexity to the known ASXL1 functions. In contrast to the positive role of ASXL1 in the cell cycle progression during early embryogenesis, ASXL1 has been speculated to be a potential tumor suppressor because of frequent mutations in various myeloid leukemia 7, 8 . Intriguingly, overexpression of EZH2 has been found in various types of human cancers, including prostate and breast cancer 35, 36 .…”

Section: Discussionmentioning

confidence: 99%

“…ASXL1 also seems to function as a tumor suppressor. Mutations of ASXL1 are often found in human diseases and are mostly linked to acute myeloid leukemia 7 , myelodysplastic syndromes and chronic myelomonocytic leukemia 8 , and Bohring-Opitz syndrome 9 . Despite the somatic ASXL1 mutations frequently reported in leukemia patients, the mechanisms by which ASXL1 mutations cause cancer are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Asxl1 deficiency in embryonic fibroblasts leads to cellular senescence via impairment of the AKT-E2F pathway and Ezh2 inactivation

Youn

Kim

Park

et al. 2017

Sci Rep

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Although ASXL1 mutations are frequently found in human diseases, including myeloid leukemia, the cell proliferation-associated function of ASXL1 is largely unknown. Here, we explored the molecular mechanism underlying the growth defect found in Asxl1-deficient mouse embryonic fibroblasts (MEFs). We found that Asxl1, through amino acids 371 to 655, interacts with the kinase domain of AKT1. In Asxl1-null MEFs, IGF-1 was unable to induce AKT1 phosphorylation and activation; p27Kip1, which forms a ternary complex with ASXL1 and AKT1, therefore remained unphosphorylated. Hypophosphorylated p27Kip1 is able to enter the nucleus, where it prevents the phosphorylation of Rb; this ultimately leads to the down-regulation of E2F target genes as confirmed by microarray analysis. We also found that senescence-associated (SA) genes were upregulated and that SA β-gal staining was increased in Asxl1 −/− MEFs. Further, the treatment of an AKT inhibitor not only stimulated nuclear accumulation of p27Kip1 leading to E2F inactivation, but also promoted senescence. Finally, Asxl1 disruption augmented the expression of p16Ink4a as result of the defect in Asxl1-Ezh2 cooperation. Overall, our study provides the first evidence that Asxl1 both activates the AKT-E2F pathway and cooperates with Ezh2 through direct interactions at early embryonic stages, reflecting that Asxl1 disruption causes cellular senescence.The additional sex comb (Asx) gene was originally identified in Drosophila as an enhancer of trithorax group (TrxG) and Polycomb group (PcG) proteins 1 . Three paralog Asx-like (Asxl) genes have been found in mammals, encoding ASXL1, ASXL2, and ASXL3 2-4 . We recently reported that ASXL1 is mainly located in the nucleus and acts as a dual-function regulator of nuclear receptors, either cooperating with SRC1 for activation or with HP1 for repression in the presence of a ligand 5,6 . ASXL1 also seems to function as a tumor suppressor. Mutations of ASXL1 are often found in human diseases and are mostly linked to acute myeloid leukemia 7 , myelodysplastic syndromes and chronic myelomonocytic leukemia 8 , and Bohring-Opitz syndrome 9 . Despite the somatic ASXL1 mutations frequently reported in leukemia patients, the mechanisms by which ASXL1 mutations cause cancer are not fully understood. Recent studies using leukemia cells from human patients with ASXL1 mutations showed that ASXL1 interacts with histone methyltransferase EZH2, one of PRC2 members, to increase histone H3K27 tri-methylation (me3) 10 . In addition, Asxl1 deletion in mice was accompanied with reduction of H3K27me3. In contrast, loss of Bap1, one of Asxl1 binding partners, resulted in enhanced H3K27me3 level and EZH2-dependent transformation 11 , suggesting distinct, independent roles of Asxl1 and Bap1 in myeloid leukemogenesis.AKT, also called protein kinase B, was identified as the cellular counterpart of a viral oncogene. Amplified AKT isoforms has been found in several types of human cancers [12][13][14] . Not only is AKT a key regulator of cell

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“…The frequency is slightly different between single groups. The highest percentage of mutated patients can be found in chronic myelomonocytic leukemia (CMML), followed by myelofibrosis, secondary AML, MDS and de novo AML, with frequencies of about 50%, 35%, 30%, 15% and 8%, respectively [92,93]. Acquired ASXL1 mutations are frequently frameshift and nonsense, around the Gly-rich domain (amino acids 642-685) on exon 12, and cause the expression of truncated ASXL1, with loss of the PHD domain, crucial for the regulation of key genes involved in stem-cell maintenance and myeloid differentiation (Table 2, Figure 2) [94].…”

Section: Asxl1 Mutationsmentioning

confidence: 99%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.

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Prognostic significance of ASXL1 mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: A meta-analysis

Abstract: ASXL1 mutations were associated with poor prognosis in MDS, which may contribute to risk stratification and prognostic assessment in the disease.

Cited by 26 publications

References 44 publications

Prognostic significance of SETBP1 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia: A meta-analysis

Prognostic significance of SETBP1 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia: A meta-analysis

Asxl1 deficiency in embryonic fibroblasts leads to cellular senescence via impairment of the AKT-E2F pathway and Ezh2 inactivation

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

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