Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Asada, Shuhei; Goyama, Susumu; Inoue, Daichi; Shikata, Shiori; Takeda, Reina; Fukushima, Tsuyoshi; Yonezawa, Taishi; Fujino, Takeshi; Hayashi, Yasutaka; Kawabata, Kimihito C.; Fükuyama, Tsutomu; Tanaka, Yosuke; Yokoyama, Akihiko; Yamazaki, Satoshi; Kozuka‐Hata, Hiroko; Oyama, Masaaki; Kojima, Shinya; Kawazu, Masahito; Mano, Hiroyuki; Kitamura, Toshio

doi:10.1038/s41467-018-05085-9

Cited by 104 publications

(97 citation statements)

References 63 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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“…Whereas the tumor suppressive role has been attributed to BAP1's important involvement in DNA double strand breakage repair [37], there is emerging evidence that BAP1 can also promote tumor growth when it is overexpressed in particular molecular environments. For example, target genes of BAP1 deubiquitination include mutant ATRX in myeloid neoplasms [25] and Krüppellike factor 5 (KLF5) in basal-like breast cancers [24], which both become stabilized by BAP1 and consequently accelerate tumor growth [24,25]. That BAP1 interacts with KLF5 is of potential interest.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2019

Oncotarget

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Loss of the putative tumor suppressor BAP1 is a candidate biomarker for adverse prognosis in many cancer types, but conversely for improved survival in others. Studies on the expression and prognostic role of BAP1 in prostate cancer are currently lacking. We used a tissue microarray of 17,747 individual prostate cancer samples linked with comprehensive pathological, clinical and molecular data and studied the immunohistochemical expression of BAP1. BAP1 expression was typically up regulated in cancers as compared to adjacent normal prostatic glands. In 15,857 cancers, BAP1 staining was weak in 3.3%, moderate in 41.6% and strong in 17.4%. Strong BAP1 staining was associated with advanced tumor stage (p<0.0001), high classical and quantitative Gleason grade (p<0.0001), lymph node metastasis (p<0.0001), a positive surgical margin (p=0.0019) and early biochemical recurrence (p<0.0001). BAP1 expression was linked to ERG-fusion type cancers, with strong BAP1 staining in 12% of ERG-negative, but 30% of ERG-positive cancers (p<0.0001). Subset analyses in 5,415 cancers with and 4,217 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. Multivariate analysis revealed that the prognostic impact was independent of established prognostic features in ERG negative p<0.001) but not in ERG positive cancers. BAP1 expression was further linked to androgen receptor (AR) expression: Only 2% of AR-negative, but 33% of strongly AR expressing cancers had strong BAP1 expression (p<0.0001). In conclusion, this study shows that BAP1 up regulation is linked to prostate cancer progression and aggressiveness.

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“…Recently, we have reported that the mutant ASXL1 and BAP1 form a hyperactive complex to promote myeloid transformation (Fig. 2) [60]. As with wildtype ASXL1, the mutant ASXL1 also contains the ASXH domain (also referred to as DEUBAD), which is essential for interacting with BAP1.…”

Section: The Monoubiquitinated Mutant Asxl1 Forms a Hyperactive Complmentioning

confidence: 99%

“…Bap1-depleted mice showed substantial retention of H2AK119ub and increased the level of H3K27me3 [55]. On the other hand, expression of the mutant ASXL1 results in dysregulation of HOXA gene and reduction of both H2AK119ub and H3K27me3 at HOXA loci [43,45,60,65]. In classical view, CBX recognizes H3K27me3 catalyzed by PRC2 complex followed by recruiting of PRC1 complex to H3K27me3 and subsequent ubiquitination of H2AK119 [73].…”

Section: Regulation Of Hoxa Gene Expression By H2ak119ub Modificationmentioning

confidence: 99%

Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

Asada

Kitamura

2018

Int J Hematol

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An epigenetic modulator Additional sex combs-like 1 (ASXL1) is recurrently mutated in myeloid neoplasms such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). ASXL1 mutations are also frequently detected in clonal hematopoiesis with indeterminate potential (CHIP), which is the clonal expansion of premalignant hematopoietic cells without any evidence of hematological malignancies. Thus, understanding the roles of ASXL1 in hematopoiesis and myeloid neoplasms is a clinically crucial issue. ASXL1 mutations in hematological neoplasms are typically frameshift or nonsense mutations and occur near the 5′ end of the last exon, thereby the transcripts would escape from nonsense-mediated decay, Indeed, we identified the C-terminally truncated mutant protein of ASXL1 in several cell lines derived from patients with myeloid leukemia. In mouse models, expression of the mutant ASXL1 results in impaired hematopoiesis and promotes development of myeloid neoplasms. In addition, recent findings from biochemical analysis have demonstrated that the mutant ASXL1 protein gains new functions including enhancing catalytic activity of BRCA1-associated protein 1 (BAP1), resulting in reduction of H2AK119ub and aberrant gene expression essential for myeloid transformation. In this review, we will focus on the pivotal roles of the mutant ASXL1 on histone modifications and myeloid transformation.

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Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Cited by 104 publications

References 63 publications

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Clinical implications of recurrent gene mutations in acute myeloid leukemia

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Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

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