Molecular characterization of EZH2 mutant patients with myelodysplastic/myeloproliferative neoplasms

Rinke, Jenny; Müller, Jörg P.; Blaess, Markus; Chase, Andrew; Meggendorfer, Manja; Schäfer, Vivien; Winkelmann, Nils; Haferlach, Claudia; Cross, Nicholas C.P.; Hochhaus, Andreas; Ernst, Thomas

doi:10.1038/leu.2017.190

Cited by 24 publications

(27 citation statements)

References 39 publications

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“…Additional RAS-signaling pathway activation in form of an internal tandem duplication of Fms Related Receptor Tyrosine Kinase 3 (FLT3-ITD), frequently detected in AML and associated with a worse prognosis, resulted in aggressive lympho-myeloid leukemia [62]. EZH2 mutations also frequently co-occur with TET2 mutations [47,48,60]. Murine analyses conducted by Muto et al revealed that EZH2 or TET2 deficiency alone is sufficient to induce an MDS/MPN phenotype with lethality during long observation periods, while depletion of both EZH2 and TET2 synergistically advances myelodysplasia and accelerates the progression of both MDS and MDS/MPN.…”

Section: Mutual Exclusion and Concomitance Of Ezh2 And Other Leukemiamentioning

confidence: 99%

EZH2 in Myeloid Malignancies

Rinke

Chase

Cross

et al. 2020

Cells

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Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission.

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Section: Mutual Exclusion and Concomitance Of Ezh2 And Other Leukemiamentioning

confidence: 99%

EZH2 in Myeloid Malignancies

Rinke

Chase

Cross

et al. 2020

Cells

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“…Inactivating mutations of EZH2 are also observed in MDS, which are associated with its decreased expression level. [39][40][41][42][43] Another novel target of mis-splicing is LUC7L2, a spliceosome gene which is located on chromosome 7q34 and is also mutated infrequently in MDS. 34,44 Usage of cryptic splice site in SRSF2 del and P95 mutant samples produces transcripts with premature stop codon, potentially leading to decreased expression of LUC7L2.…”

Section: Gene Expression Profiling Reveals Dysregulated Heme Metabomentioning

confidence: 99%

Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Madan

Zhou

et al. 2019

American J Hematol

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Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in >50% of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of MDS bone marrow samples harboring spliceosome mutations (including hotspot alterations of SF3B1, SRSF2 and

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“…Earlier, we and others have shown that Rac GTPases critically regulate leukemia cell engraftment and survival (15)(16)(17)(18). VAV3, Rho/Rac GTPase GEF, was implicated in leukemogenesis (41,42). DOCK2 is a noncanonical GEF for Rac GTPases, and DOCK2 inhibition in vivo attenuates AML cell survival (43,44).…”

Section: Discussionmentioning

confidence: 98%

SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia

Chatterjee

Biswas

Boila

et al. 2018

Molecular Cancer Research

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SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although genes are altered in approximately 25% of human malignancies, evidences showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNF SMARCC1 (BAF155), an intact core component of SWI/SNF, colocalized with H3K27Ac to target oncogenic loci in primary AML cells. Interestingly, gene ontology (GO) term and pathway analysis suggested that SMARCC1 occupancy was enriched on genes regulating Rac GTPase activation, cell trafficking, and AML-associated transcriptional dysregulation. Transcriptome profiling revealed that expression of these genes is upregulated in primary AML blasts, and loss-of-function studies confirmed transcriptional regulation of Rac GTPase guanine nucleotide exchange factors () by SMARCB1. Mechanistically, loss of SMARCB1 increased recruitment of SWI/SNF and associated histone acetyltransferases (HAT) to target loci, thereby promoting H3K27Ac and gene expression. Together, SMARCB1 deficiency induced for Rac GTPase activation and augmented AML cell migration and survival. Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNF function in maintaining an oncogenic gene expression program in AML. Loss of SMARCB1 in AML associates with SWI/SNF nucleation, which in turn promotes Rac GTPase expression, Rac activation, migration, and survival of AML cells, highlighting SWI/SNF downstream signaling as important molecular regulator in AML. .

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Molecular characterization of EZH2 mutant patients with myelodysplastic/myeloproliferative neoplasms

Cited by 24 publications

References 39 publications

EZH2 in Myeloid Malignancies

EZH2 in Myeloid Malignancies

Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia

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