Emerging role of noncanonical polycomb repressive complexes in normal and malignant hematopoiesis

Isshiki, Yusuke; Iwama, Atsushi

doi:10.1016/j.exphem.2018.10.008

Cited by 16 publications

(18 citation statements)

References 42 publications

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“…The BCL6 co-repressor (BCOR) gene is located on chromosome Xp11.4 and encodes a transcription regulatory factor that was initially identified as an interactor partner of the germinal center-associated BCL6 protein [1,2]. The BCOR protein is located in the nucleus [3] where exerts its function as a member of the non-canonical multimeric polycomb group repressive complex 1 (PRC1) which is recruited to the target sites independently of H3K27me3 [4]. This complex is involved in the control of various biological processes, including pluripotency, reprogramming, and hematopoiesis [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…The BCOR protein is located in the nucleus [3] where exerts its function as a member of the non-canonical multimeric polycomb group repressive complex 1 (PRC1) which is recruited to the target sites independently of H3K27me3 [4]. This complex is involved in the control of various biological processes, including pluripotency, reprogramming, and hematopoiesis [4,5]. Relatively high frequency of BCOR mutations has been reported in aplastic anemia suggesting that these genetic events may confer a selective advantage in the context of aplastic anemia autoimmune environment, although they do not appear to be associated with an increased risk of secondary AML/MDS [6].…”

Section: Introductionmentioning

confidence: 99%

“…We previously found that about 40% of AML patients with BCOR mutations also carry mutations of DNMT3a [9] catalyzing the addition of methyl groups to CpG dinucleotides. Because BCOR and DNMT3A are both epigenetic modifiers [4,20,21], mutations of these genes could promote AML through a synergistic mechanism [9]. Murine hematopoietic cells lacking Dnmt3a have thousands of focal, "canonically" located, hypomethylated regions that are amenable to be "repaired" with partial correction of dysregulated gene expression and myeloid skewing [22].…”

Section: Introductionmentioning

confidence: 99%

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Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

et al. 2020

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Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor−/− knockout mouse model characterized by impaired erythroid development (macrocytosis and anemia) and enhanced thrombopoiesis, which are both features of myelodysplasia/myeloproliferative neoplasms. We then created and characterized double Bcor−/−/Dnmt3a−/− knockout mice. Interestingly, these animals developed a fully penetrant acute erythroid leukemia (AEL) characterized by leukocytosis secondary to the expansion of blasts expressing c-Kit+ and the erythroid marker Ter119, macrocytic anemia and progressive reduction of the thrombocytosis associated with loss of Bcor alone. Transcriptomic analysis of double knockout bone marrow progenitors revealed that aberrant erythroid skewing was induced by epigenetic changes affecting specific transcriptional factors (GATA1-2) and cell-cycle regulators (Mdm2, Tp53). These findings prompted us to investigate the efficacy of demethylating agents in AEL, with significant impact on progressive leukemic burden and mice overall survival. Information gained from our model expands the knowledge on the biology of AEL and may help designing new rational treatments for patients suffering from this high-risk leukemia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

et al. 2020

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“…KDM2B is a member of the polycomb repressive complex (PRC1.1) and interacts with SS18-SSX1 [ 23 ]. Deregulation of PRC1.1 was reported in various human malignancies, such as gynecologic cancer and myelodysplastic syndrome [ 24 ]. As shown in Figure 2 C, conservation of the EPC1 protein interaction domain of EPC1 as a NuA4 member and the KDM2B catalytic domain suggests that fusion affects the functions of both the Nu4A and PRC1.1 complexes.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model

Teramura

Tanaka

Yamazaki

et al. 2020

Cancers

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Fusion genes induced by chromosomal aberrations are common mutations causally associated with bone and soft tissue sarcomas (BSTS). These fusions are usually disease type-specific, and identification of the fusion genes greatly helps in making precise diagnoses and determining therapeutic directions. However, there are limitations in detecting unknown fusion genes or rare fusion variants when using standard fusion gene detection techniques, such as reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). In the present study, we have identified 19 novel fusion genes using target RNA sequencing (RNA-seq) in 55 cases of round or spindle cell sarcomas in which no fusion genes were detected by RT-PCR. Subsequent analysis using Sanger sequencing confirmed that seven out of 19 novel fusion genes would produce functional fusion proteins. Seven fusion genes detected in this study affect signal transduction and are ideal targets of small molecule inhibitors. YWHAE-NTRK3 expression in mouse embryonic mesenchymal cells (eMCs) induced spindle cell sarcoma, and the tumor was sensitive to the TRK inhibitor LOXO-101 both in vitro and in vivo. The combination of target RNA-seq and generation of an ex vivo mouse model expressing novel fusions provides important information both for sarcoma biology and the appropriate diagnosis of BSTS.

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“…Gain-of-function mutations in EZH2 play an oncogenic role in the development of B-cell lymphoma, while EZH2 also has a tumor suppressive role as missense and frame-shift mutations in EZH2 that abrogate its methyltransferase activity are frequently observed in MDS, MPN, and MDS/MPN overlap disorders [6]. There is also a tumor suppressive function of PRC1.1, a nonconical PRC1, in the pathogenesis of myeloid malignancies [7]. In this review, we focus on recent findings on the role of PRCs in the pathogenesis of myeloproliferative neoplasms (MPN) and the therapeutic impacts of targeting the pathological function of PRCs in MPN and related hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

Deregulated Polycomb functions in myeloproliferative neoplasms

2019

Self Cite

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Polycomb proteins function in the maintenance of gene silencing via post-translational modifications of histones and chromatin compaction. Genetic and biochemical studies have revealed that the repressive function of Polycomb repressive complexes (PRCs) in transcription is counteracted by the activating function of Trithorax-group complexes; this balance fine-tunes the expression of genes critical for development and tissue homeostasis. The function of PRCs is frequently dysregulated in various cancer cells due to altered expression or recurrent somatic mutations in PRC genes. The tumor suppressive functions of EZH2-containing PRC2 and a PRC2-related protein ASXL1 have been investigated extensively in the pathogenesis of hematological malignancies, including myeloproliferative neoplasms (MPN). BCOR, a component of non-canonical PRC1, suppresses various hematological malignancies including MPN. In this review, we focus on recent findings on the role of PRCs in the pathogenesis of MPN and the therapeutic impact of targeting the pathological functions of PRCs in MPN.

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Emerging role of noncanonical polycomb repressive complexes in normal and malignant hematopoiesis

Cited by 16 publications

References 42 publications

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model

Deregulated Polycomb functions in myeloproliferative neoplasms

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