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1.
Blood Adv ; 4(5): 845-854, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32126143

RESUMO

Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.

2.
BMC Cardiovasc Disord ; 20(1): 116, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138671

RESUMO

BACKGROUND: Left ventricular reverse remodeling (LVRR) has been detected in non-ischemic dilated cardiomyopathy (NIDCM) patients following optimal treatment. However, its prediction with only conventional modalities is often difficult. This study sought to examine whether RNA sequencing (RNA-seq) of myocardium tissue samples could predict LVRR in NIDCM. METHODS: A total of 17 advanced NIDCM patients with left ventricular ejection fraction (LVEF) below 30% who underwent cardiac biopsy from Left ventricle (LV) were prospectively recruited. They received optimal treatment and followed with echocardiogram every 6 months. Based on LVRR status after 12 months of treatment, patients were divided into the reverse remodeling (RR) or non-RR group. Tissue samples were analyzed by RNA-seq, and a functional analysis of differentially expressed genes was carried out. RESULTS: There were eight and nine patients in the RR and non-RR groups, respectively. No difference was found in age, sex, disease duration, LV end-diastolic diameter, and LVEF between the two groups. There were 155 genes that were differentially expressed between the two groups. Nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunit (NDUF)S5 and Growth arrest and DNA-damage-inducible protein (GADD)45G, along with several genes related to the mitochondrial respiratory chain and ribosome, were significantly downregulated in the RR as compared to the non-RR group. CONCLUSION: GADD45G and NDUFS5 are potential biomarkers for LVRR in patients with advanced NIDCM.

3.
Biochem Biophys Res Commun ; 521(3): 612-619, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31679686

RESUMO

Polycomb-group proteins are critical regulators of stem cells. We previously demonstrated that Bmi1, a component of polycomb repressive complex 1, defines the regenerative capacity of hematopoietic stem cells (HSCs). Here, we attempted to ameliorate the age-related decline in HSC function by modulating Bmi1 expression. The forced expression of Bmi1 did not attenuate myeloid-biased differentiation of aged HSCs. However, single cell transplantation assays revealed that the sustained expression of Bmi1 augmented the multi-lineage repopulating capacity of aged HSCs. Chromatin immunoprecipitation-sequencing of Bmi1 combined with an RNA sequence analysis showed that the majority of Bmi1 direct target genes are developmental regulator genes marked with a bivalent histone domain. The sustained expression of Bmi1 strictly maintained the transcriptional repression of their target genes and enforced expression of HSC signature genes in aged HSCs. Therefore, the manipulation of Bmi1 expression is a potential approach against impairments in HSC function with aging.

4.
Cancer Sci ; 110(12): 3695-3707, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571328

RESUMO

Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3 to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results reveal some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for multiple myeloma.


Assuntos
Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Complexo Repressor Polycomb 2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sinergismo Farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Proteína Forkhead Box O3/fisiologia , Humanos , Mieloma Múltiplo/patologia , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/fisiologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/fisiologia , Piridonas/uso terapêutico
5.
Blood Adv ; 3(17): 2537-2549, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31471323

RESUMO

KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.

8.
Exp Hematol ; 76: 24-37, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31408689

RESUMO

The polycomb group protein Bmi1 maintains hematopoietic stem cell (HSC) functions. We previously reported that Bmi1-deficient mice exhibited progressive fatty changes in bone marrow (BM). A large portion of HSCs reside in the perivascular niche created partly by endothelial cells and leptin receptor+ (LepR+) BM stromal cells. To clarify how Bmi1 regulates the HSC niche, we specifically deleted Bmi1 in LepR+ cells in mice. The Bmi1 deletion promoted the adipogenic differentiation of LepR+ stromal cells and caused progressive fatty changes in the BM of limb bones with age, resulting in reductions in the numbers of HSCs and progenitors in BM and enhanced extramedullary hematopoiesis. This adipogenic change was also evident during BM regeneration after irradiation. Several adipogenic regulator genes appeared to be regulated by Bmi1. Our results indicate that Bmi1 keeps the adipogenic differentiation program repressed in BM stromal cells to maintain the integrity of the HSC niche.


Assuntos
Adipogenia/fisiologia , Células-Tronco Hematopoéticas/citologia , Complexo Repressor Polycomb 1/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Nicho de Células-Tronco , Animais , Medula Óssea/patologia , Medula Óssea/fisiologia , Linhagem Celular , Autorrenovação Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo Repressor Polycomb 1/deficiência , Proteínas Proto-Oncogênicas/deficiência , Receptores para Leptina/análise , Regeneração , Células Estromais/química , Células Estromais/patologia
9.
Proc Natl Acad Sci U S A ; 116(33): 16404-16409, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31358627

RESUMO

Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite having shortened telomeres. Aged SSCs showed increased Wnt7b expression, which was associated with decreased Polycomb complex 2 activity. Our results suggest that aberrant Wnt7b expression activated c-jun N-terminal kinase (JNK), which down-regulated mitochondria numbers by suppressing Ppargc1a Down-regulation of Ppargc1a probably decreased reactive oxygen species and enhanced glycolysis. Analyses of the Klotho-deficient aging mouse model and 2-y-old aged rats confirmed JNK hyperactivation and increased glycolysis. Therefore, not only microenvironment but also intrinsic activation of JNK-mediated glycolysis contributes to SSC aging.

10.
Stem Cells Int ; 2019: 9789240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31065285

RESUMO

The "bivalent domain," a distinctive histone modification signature, is characterized by repressive trimethylation of histone H3 at lysine 27 (H3K27me3) and active trimethylation of histone H3 at lysine 4 (H3K4me3) marks. Maintenance and dynamic resolution of these histone marks play important roles in regulating differentiation processes in various stem cell systems. However, little is known regarding their roles in hepatic stem/progenitor cells. In the present study, we conducted the chromatin immunoprecipitation (ChIP) assay followed by high-throughput DNA sequencing (ChIP-seq) analyses in purified delta-like 1 protein (Dlk+) hepatic stem/progenitor cells and successfully identified 562 genes exhibiting bivalent domains within 2 kb of the transcription start site. Gene ontology analysis revealed that these genes were enriched in developmental functions and differentiation processes. Microarray analyses indicated that many of these genes exhibited derepression after differentiation toward hepatocyte and cholangiocyte lineages. Among these, 72 genes, including Cdkn2a and Sox4, were significantly upregulated after differentiation toward hepatocyte or cholangiocyte lineages. Knockdown of Sox4 in Dlk+ cells suppressed colony propagation and resulted in increased numbers of albumin+/cytokeratin 7+ progenitor cells in colonies. These findings implicate that derepression of Sox4 expression is required to induce normal differentiation processes. In conclusion, combined ChIP-seq and microarray analyses successfully identified bivalent genes. Functional analyses of these genes will help elucidate the epigenetic machinery underlying the terminal differentiation of hepatic stem/progenitor cells.

11.
Blood Adv ; 3(7): 1047-1060, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30944097

RESUMO

Chronic myelomonocytic leukemia (CMML) constitutes a hematopoietic stem cell (HSC) disorder characterized by prominent monocytosis and myelodysplasia. Although genome sequencing has revealed the CMML mutation profile, the mechanism of disease development remains unclear. Here we show that aberrant histone acetylation by nucleoporin-98 (NUP98)-HBO1, a newly identified fusion in a patient with CMML, is sufficient to generate clinically relevant CMML pathogenesis. Overexpression of NUP98-HBO1 in murine HSC/progenitors (HSC/Ps) induced diverse CMML phenotypes, such as severe leukocytosis, increased CD115+ Ly6Chigh monocytes (an equivalent subpopulation to human classical CD14+ CD16- monocytes), macrocytic anemia, thrombocytopenia, megakaryocyte-lineage dysplasia, splenomegaly, and cachexia. A NUP98-HBO1-mediated transcriptional signature in human CD34+ cells was specifically activated in HSC/Ps from a CMML patient cohort. Besides critical determinants of monocytic cell fate choice in HSC/Ps, an oncogenic HOXA9 signature was significantly activated by NUP98-HBO1 fusion through aberrant histone acetylation. Increased HOXA9 gene expression level with disease progression was confirmed in our CMML cohort. Genetic disruption of NUP98-HBO1 histone acetyltransferase activity abrogated its leukemogenic potential and disease development in human cells and a mouse model. Furthermore, treatment of azacytidine was effective in our CMML mice. The recapitulation of CMML clinical phenotypes and gene expression profile by the HBO1 fusion suggests our new model as a useful platform for elucidating the central downstream mediators underlying diverse CMML-related mutations and testing multiple compounds, providing novel therapeutic potential.

12.
Nat Commun ; 10(1): 1653, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971697

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células Dendríticas/patologia , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Proliferação de Células/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Humanos , Células Jurkat , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação Genética/genética , Irradiação Corporal Total
13.
Nucleic Acids Res ; 47(9): 4509-4520, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30892634

RESUMO

PLZF (promyelocytic leukemia zinc finger) is a transcription factor acting as a global regulator of hematopoietic commitment. PLZF displays an epigenetic specificity by recruiting chromatin-modifying factors but little is known about its role in remodeling chromatin of cells committed toward a given specific hematopoietic lineage. In murine myeloid progenitors, we decipher a new role for PLZF in restraining active genes and enhancers by targeting acetylated lysine 27 of Histone H3 (H3K27ac). Functional analyses reveal that active enhancers bound by PLZF are involved in biological processes related to metabolism and associated with hematopoietic aging. Comparing the epigenome of young and old myeloid progenitors, we reveal that H3K27ac variation at active enhancers is a hallmark of hematopoietic aging. Taken together, these data suggest that PLZF, associated with active enhancers, appears to restrain their activity as an epigenetic gatekeeper of hematopoietic aging.


Assuntos
Envelhecimento/genética , Células-Tronco Hematopoéticas/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Transcrição Genética , Animais , Diferenciação Celular/genética , Elementos Facilitadores Genéticos , Epigênese Genética/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Células Progenitoras Mieloides/metabolismo , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico/genética
14.
Blood ; 133(23): 2495-2506, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-30917958

RESUMO

Recurrent inactivating mutations have been identified in the X-linked plant homeodomain finger protein 6 (PHF6) gene, encoding a chromatin-binding transcriptional regulator protein, in various hematological malignancies. However, the role of PHF6 in normal hematopoiesis and its tumor-suppressor function remain largely unknown. We herein generated mice carrying a floxed Phf6 allele and inactivated Phf6 in hematopoietic cells at various developmental stages. The Phf6 deletion in embryos augmented the capacity of hematopoietic stem cells (HSCs) to proliferate in cultures and reconstitute hematopoiesis in recipient mice. The Phf6 deletion in neonates and adults revealed that cycling HSCs readily acquired an advantage in competitive repopulation upon the Phf6 deletion, whereas dormant HSCs only did so after serial transplantations. Phf6-deficient HSCs maintained an enhanced repopulating capacity during serial transplantations; however, they did not induce any hematological malignancies. Mechanistically, Phf6 directly and indirectly activated downstream effectors in tumor necrosis factor α (TNFα) signaling. The Phf6 deletion repressed the expression of a set of genes associated with TNFα signaling, thereby conferring resistance against the TNFα-mediated growth inhibition on HSCs. Collectively, these results not only define Phf6 as a novel negative regulator of HSC self-renewal, implicating inactivating PHF6 mutations in the pathogenesis of hematological malignancies, but also indicate that a Phf6 deficiency alone is not sufficient to induce hematopoietic transformation.


Assuntos
Autorrenovação Celular , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas Repressoras/metabolismo , Animais , Proliferação de Células/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
15.
Int J Hematol ; 110(2): 170-178, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30706327

RESUMO

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.


Assuntos
Transformação Celular Neoplásica/genética , Transtornos Mieloproliferativos/genética , Proteínas de Neoplasias/fisiologia , Proteínas do Grupo Polycomb/fisiologia , Proteínas de Ciclo Celular/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/deficiência , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Mutação com Ganho de Função , Regulação Neoplásica da Expressão Gênica , Hematopoese , Código das Histonas , Histona-Lisina N-Metiltransferase/fisiologia , Humanos , Terapia de Alvo Molecular , Proteína de Leucina Linfoide-Mieloide/fisiologia , Transtornos Mieloproliferativos/metabolismo , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Complexo Repressor Polycomb 2/antagonistas & inibidores , Proteínas do Grupo Polycomb/deficiência , Proteínas do Grupo Polycomb/genética , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Repressoras/fisiologia , Fatores de Transcrição/fisiologia
16.
Leukemia ; 33(7): 1723-1735, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30635632

RESUMO

POEMS syndrome is a rare paraneoplastic disease associated with monoclonal plasma cells; however, the pathogenic importance of plasma cells remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing was performed in 11 cases and found a total of 308 somatic mutations in 285 genes. Targeted sequencing was performed in all 20 cases and identified 20 mutations in 7 recurrently mutated genes, namely KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS), suggesting a partial overlap in the early development of MGUS and POEMS syndrome. RNA sequencing revealed a transcription profile specific to POEMS syndrome when compared with normal plasma cells, MGUS and MM. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating unique function of clonal plasma cells in its pathogenesis.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Mutação , Recidiva Local de Neoplasia/genética , Síndrome POEMS/genética , Plasmócitos/metabolismo , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/genética , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Síndrome POEMS/tratamento farmacológico , Síndrome POEMS/patologia , Plasmócitos/patologia , Prognóstico , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
17.
Exp Hematol ; 68: 10-14, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30554637

RESUMO

Polycomb group (PcG) proteins are the key epigenetic regulators of normal hematopoiesis and the dysregulation of their functions is closely involved in the pathogenesis of hematological malignancies. These proteins function in the multimeric complexes called polycomb repressive complex (PRC) 1 and 2. In addition to canonical PRC1, four noncanonical PRC1 complexes have been identified. In contrast to canonical PRC1, which is recruited to its target sites in a manner dependent on H3K27me3, noncanonical PRC1 complexes are recruited to their target sites independently of H3K27me3. Among them, PRC1.1, consisting of PCGF1, RING1A/B, KDM2B, and BCL6 corepressor (BCOR) or BCLRL1, regulates diverse biological processes, including pluripotency, reprogramming, and hematopoiesis. PRC1.1 has been implicated in myelopoiesis and lymphopoiesis and is targeted by somatic gene mutations in various hematological malignancies. These findings revealed the more complex regulation of epigenetic cellular memory by PcG proteins than we expected and propose PRC1.1 as a novel therapeutic target in hematological malignancies.


Assuntos
Neoplasias Hematológicas/fisiopatologia , Hematopoese/fisiologia , Proteínas do Grupo Polycomb/fisiologia , Animais , Células-Tronco Embrionárias/metabolismo , Previsões , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Código das Histonas/genética , Código das Histonas/fisiologia , Humanos , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Mutação , Células Mieloides/citologia , Células Mieloides/metabolismo , Proteínas de Neoplasias/fisiologia , Proteínas do Grupo Polycomb/genética , Dedos de Zinco/fisiologia
18.
iScience ; 9: 161-174, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30396150

RESUMO

Polycomb repressive complex (PRC) 2 represses transcription through histone H3K27 trimethylation (H3K27me3). We previously reported that the hematopoietic-cell-specific deletion of Ezh2, encoding a PRC2 enzyme, induced myelodysplastic syndrome (MDS) in mice, whereas the concurrent Ezh1 deletion depleted hematopoietic stem and progenitor cells (HSPCs). We herein demonstrated that mice with only one Ezh1 allele (Ezh1+/-Ezh2Δ/Δ) maintained HSPCs. A chromatin immunopreciptation sequence analysis revealed that residual PRC2 preferentially targeted genes with high levels of H3K27me3 and H2AK119 monoubiquitination (H2AK119ub1) in HSPCs (designated as Ezh1 core target genes), which were mostly developmental regulators, and maintained H3K27me3 levels in Ezh1+/-Ezh2Δ/Δ HSPCs. Even upon the complete depletion of Ezh1 and Ezh2, H2AK119ub1 levels were largely retained, and only a minimal number of Ezh1 core targets were de-repressed. These results indicate that genes marked with high levels of H3K27me3 and H2AK119ub1 are the core targets of polycomb complexes in HSPCs as well as MDS stem cells.

19.
Rinsho Ketsueki ; 59(10): 2036-2041, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30305506

RESUMO

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis including dyserythropoiesis. Recently, several signaling pathways have been implicated in dyserythropoiesis in MDS, such as the p53-S100A8/9-TLR4 pathway, which is involved in ineffective erythropoiesis in 5q- syndrome. Somatic mutations that target SF3B1, which encodes a component of the mRNA splicing machinery, have been identified in approximately 85% of patients with MDS presenting with ring sideroblasts (MDS-RS). SF3B1 mutations confer a change-of-function and cause aberrant splicing of genes that may be involved in the pathogenesis of MDS-RS. Recurrent mutations have also been identified in epigenetic regulator genes in MDS, including polycomb repressive complex 2 (PRC2) genes, and the loss of Ezh2, an enzymatic component of PRC2, enhances ineffective hematopoiesis and induces impaired erythropoiesis. A better understanding of the molecular mechanisms underlying dyserythropoiesis in MDS may lead to innovative novel therapeutic modalities.


Assuntos
Eritropoese , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Processamento de RNA , Anemia Macrocítica , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Humanos , Mutação , Fosfoproteínas , Complexo Repressor Polycomb 2/genética , Fatores de Processamento de RNA
20.
Blood ; 132(23): 2470-2483, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30228234

RESUMO

BCOR, encoding BCL-6 corepressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (Bcor ΔE4/y ) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (Bcor ΔE9-10/y ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. Bcor ΔE9-10/y mice developed lethal T-ALL in a similar manner to Bcor ΔE4/y mice, whereas Bcor ΔE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2 Tet2 Δ/Δ Bcor ΔE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2 Δ/Δ Bcor ΔE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/myeloproliferative neoplasms in secondary recipients. Transcriptional profiling revealed the derepression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in Bcor ΔE9-10/y progenitor cells and the activation of p53 target genes specifically in MDS erythroblasts where massive apoptosis occurred. Our results reveal a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency on the initiation and progression of MDS.


Assuntos
Sequência de Aminoácidos , Éxons , Síndromes Mielodisplásicas , Proteínas Repressoras , Deleção de Sequência , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Knockout , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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