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1.
Cancer Immunol Immunother ; 72(8): 2635-2648, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37069353

RESUMO

Dysfunctional anti-tumor immunity has been implicated in the pathogenesis of mature B cell neoplasms, such as multiple myeloma and B cell lymphoma; however, the impact of exhausted T cells on disease development remains unclear. Therefore, the present study investigated the features and pathogenetic significance of exhausted T cells using a mouse model of de novo mature B cell neoplasms, which is likely to show immune escape similar to human patients. The results revealed a significant increase in PD-1+ Tim-3- and PD-1+ Tim-3+ T cells in sick mice. Furthermore, PD-1+ Tim-3+ T cells exhibited direct cytotoxicity with a short lifespan, showing transcriptional similarities to terminally exhausted T cells. On the other hand, PD-1+ Tim-3- T cells not only exhibited immunological responsiveness but also retained stem-like transcriptional features, suggesting that they play a role in the long-term maintenance of anti-tumor immunity. In PD-1+ Tim-3- and PD-1+ Tim-3+ T cells, the transcription factors Tox and Nr4a2, which reportedly contribute to the progression of T cell exhaustion, were up-regulated in vivo. These transcription factors were down-regulated by IMiDs in our in vitro T cell exhaustion analyses. The prevention of excessive T cell exhaustion may maintain effective anti-tumor immunity to cure mature B cell neoplasms.


Assuntos
Linfoma de Células B , Mieloma Múltiplo , Animais , Humanos , Receptor Celular 2 do Vírus da Hepatite A , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Modelos Animais de Doenças , Fatores de Transcrição
2.
Rinsho Ketsueki ; 64(7): 581-585, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-37544716

RESUMO

POEMS syndrome is a rare monoclonal plasma cell disorder with unique symptoms distinct from other plasma cell neoplasms. To identify and find the transcriptional features of clonal plasma cells in POEMS syndrome (POEMS clones), single-cell RNA sequencing was performed on patient-derived bone marrow plasma cells. POEMS clones were identified in 5 out of 10 patients, and the proportions of POEMS clones in the plasma cells were markedly smaller than that of other plasma cell malignancies such as multiple myeloma and MGUS. The transcriptional features of POEMS clones differed from those of other plasma cell diseases, and representative MM-related oncogenes were not upregulated in POEMS clones. Notably, POEMS clones are negative for CD19 and express significantly lower MHC-II levels than normal plasma cells; thus, CD19- HLA-DRlo is confirmed as a useful marker to identify POEMS clones in patients. These findings unveil the unique features of POEMS clones and contribute to the understanding of the pathogenesis of POEMS syndrome.


Assuntos
Mieloma Múltiplo , Síndrome POEMS , Paraproteinemias , Humanos , Plasmócitos/patologia , Síndrome POEMS/genética , Síndrome POEMS/diagnóstico , Mieloma Múltiplo/patologia , Células Clonais/patologia , Análise de Sequência de RNA
3.
Gan To Kagaku Ryoho ; 48(3): 367-369, 2021 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-33790159

RESUMO

A 72-year-old woman was admitted to our hospital because of symptoms of bleeding diathesis such as hematuria and purpura. A blood test revealed disseminated intravascular coagulation(DIC). Upper gastrointestinal endoscopy showed advanced gastric cancer. Bone marrow aspiration cytology demonstrated diffuse hyperplasia of large atypical cells, and metastasis of the epithelial tumor was suspected on immunohistochemical examination. She was diagnosed with disseminated carcinomatosis of the bone marrow associated with gastric cancer accompanied by DIC. She was treated with weekly infusion of methotrexate 100 mg/m2 plus 5-fluorouracil 600 mg/m2 for 4 courses; and she completely recovered from DIC. She received oral tegafur/gimeracil/oteracil as an outpatient. However, DIC recurred 126 days after the initial chemotherapy, and 5-fluorouracil plus cisplatin was administered subsequently. After 1 course, she died 166 days after the initial chemotherapy. Although the prognosis of patients with disseminated carcinomatosis of the bone marrow associated with gastric cancer accompanied by DIC is extremely poor, this case shows that secession of DIC and prognostic improvement by chemotherapy could occur. Chemotherapy could be considered a potentially effective treatment in this case.


Assuntos
Neoplasias da Medula Óssea , Coagulação Intravascular Disseminada , Neoplasias Peritoneais , Neoplasias Gástricas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea , Neoplasias da Medula Óssea/complicações , Neoplasias da Medula Óssea/tratamento farmacológico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Feminino , Humanos , Recidiva Local de Neoplasia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico
4.
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
5.
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
6.
J Thromb Thrombolysis ; 48(1): 141-148, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30673940

RESUMO

Anti-platelet agents or anticoagulants are administered for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) to prevent thrombotic events (TEs). However, there is a discrepancy between current guidelines and clinical practice in thromboprophylaxis and the varied incidence of TEs depending on patient cohort. Therefore, a consensus on the optimal thromboprophylactic strategy is needed. To determine an appropriate strategy for the prevention of TEs in MM patients receiving IMiDs, we performed a retrospective single-institution analysis. In total, 95 MM patients (62% male, median age 65 years, range 30-85 years) from November 2008 to January 2018 were recruited, and 140 cases were analyzed in the medical-record-based study. Thromboprophylactic drugs were given to 69% of patients, anti-platelet agents to 66%, and anticoagulants to 3.0%. Seven TEs (5.0%) and six bleeding events (4.3%) were observed, but no patients died from thrombohemorrhage. The median follow-up period was 184 days (range 21-2224), and the cumulative TE incidence was 1.7% at 3 months, 7.0% at 1 year, and 12.5% at 3 years. Multivariate analysis determined that age > 70 years (p = 0.012) and BMI < 18.5 kg/m2 (p = 0.042) were the significant risk factors of TE. A low incidence of TEs was observed despite the low adherence to guideline recommendations for anticoagulant administration. These results suggest that anti-platelet agents are sufficient for thromboprophylaxis. A high-risk group of TEs in MM patients receiving IMiDs was identified, and a larger study is needed to confirm these findings.


Assuntos
Quimioprevenção/métodos , Imunomodulação , Mieloma Múltiplo/complicações , Tromboembolia Venosa/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Índice de Massa Corporal , Feminino , Hemorragia/induzido quimicamente , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/prevenção & controle
7.
Biol Blood Marrow Transplant ; 23(2): 361-363, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27840209

RESUMO

Although autologous stem cell transplantation can achieve excellent responses in patients with POEMS syndrome, the optimal regimen for peripheral blood stem cell (PBSC) collection is still controversial. We retrospectively investigated the safety and efficacy of 41 PBSC collecting procedures in 37 patients with POEMS syndrome. PBSC mobilization was performed using cyclophosphamide + granulocyte colony-stimulating factor (G-CSF) (CG, n = 14) or G-CSF alone (G, n = 27). Twelve (85.7%) patients in the CG group and all (100%) patients in the G group received induction chemotherapy before PBSC collection. The proportions of good mobilizers (≥2.0 × 106 CD34+ cells/kg) were comparable between the 2 groups (CG versus G: 78.6% versus 70.4%, P = .71). Two (14.3%) patients in the CG group developed severe capillary leak symptoms during the PBSC mobilization period, whereas no patient in the G group experienced severe adverse events. Appropriate induction therapies followed by the G-CSF monotherapy compose an optimal strategy for PBSC collection.


Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Síndrome POEMS/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Ascite/induzido quimicamente , Contagem de Células Sanguíneas , Avaliação de Medicamentos , Feminino , Febre/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/induzido quimicamente , Estudos Retrospectivos
8.
Jpn J Clin Oncol ; 47(11): 1047-1054, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973362

RESUMO

BACKGROUND: The efficacy of conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been controversial as post-remission therapies for adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. METHODS: We retrospectively analyzed 96 adolescent and adult cases of Philadelphia chromosome-negative acute lymphoblastic leukemia to evaluate whether allo-HSCT should be performed after first complete remission (1CR). RESULTS: In total, 34 patients received chemotherapy followed by allo-HSCT (HSCT group) and 62 received chemotherapy alone (chemotherapy group). No significant differences in the event-free survival (EFS) or overall survival were observed between the two groups. In the chemotherapy group, use of pediatric regimens was significantly associated with favorable EFS, while high white blood cell (WBC) count and CD20 positivity were associated with poor outcome. In patients who received pediatric regimens, subsequent allo-HSCT did not influence EFS. In patients who received conventional chemotherapy (adult regimen), subsequent allo-HSCT did not improve EFS. High WBC count and CD20 positivity were also significantly associated with poor EFS in patients who received adult regimens. Patients with low WBC count and absence of CD20 who received adult regimens did not benefit from allo-HSCT. CONCLUSIONS: Allo-HSCT may not be required in the pediatric regimen-eligible patients; however, pediatric regimen-ineligible patients with either CD20 positivity or high WBC count should receive allo-HSCT after achieving 1CR. This study was registered at http://www.umin.ac.jp/ctr/ as #C000016287.


Assuntos
Antígenos CD20/análise , Contagem de Leucócitos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Rinsho Ketsueki ; 57(5): 624-9, 2016 05.
Artigo em Japonês | MEDLINE | ID: mdl-27263789

RESUMO

A 23-year-old woman presented with a persistent fever and shortness of breath. Computed tomography showed marked pericardial effusion, hepatosplenomegaly, and cervical and mediastinal lymph node swelling. Epstein-Barr virus (EBV) antibody titers were abnormally elevated, and the copy number of EBV-DNA was increased in peripheral blood. Based on these observations, she was diagnosed with chronic active EBV infection (CAEBV). The EBV-infected cells in her peripheral blood were CD4(+)T lymphocytes. Fever and pericardial effusion improved following treatment with a combination of prednisolone, etoposide, and cyclosporine; however, peripheral blood EBV-DNA levels remained high. The patient underwent allogeneic peripheral blood stem cell transplantation from an EBV-seronegative, HLA-matched sibling donor, with fludarabine and melphalan conditioning. The post-transplantation course was uneventful, except for mild skin acute graft-versus-host disease (grade 2). EBV-DNA became undetectable in peripheral blood 98 days post transplantation. She has since been in good health without disease recurrence. CAEBV is a potentially fatal disease caused by persistent EBV infection of T lymphocytes or natural killer cells, thus requiring prompt treatment and allogeneic transplantation. Pericardial effusion is rarely observed in CAEBV and can impede its diagnosis. Therefore, we should be aware that patients may present with marked pericardial effusion as an initial manifestation of CAEBV.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4/fisiologia , Derrame Pericárdico/etiologia , Transplante de Células-Tronco de Sangue Periférico , Doença Crônica , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Transplante Homólogo , Adulto Jovem
11.
Sci Rep ; 14(1): 10362, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710832

RESUMO

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes) is a rare systemic disorder characterized by various symptoms caused by underlying plasma cell (PC) dyscrasia. Detection of monoclonal PCs is mandatory for the diagnosis of POEMS syndrome; however, the usefulness of EuroFlow-based next-generation flow cytometry (EuroFlow-NGF) in POEMS syndrome for detecting monoclonal PCs in bone marrow (BM) and the gating strategy suitable for flow cytometry study of POEMS syndrome remain unknown. We employed EuroFlow-NGF-based single-tube eight-color multiparameter flow cytometry (MM-flow) and established a new gating strategy (POEMS-flow) to detect the monoclonal PCs in POEMS syndrome, gating CD38 broadly from dim to bright and CD45 narrowly from negative to dim compared to MM-flow. MM-flow detected monoclonal PCs in 9/25 (36.0%) cases, including 2/2 immunofixation electrophoresis (IFE)-negative cases (100%). However, POEMS-flow detected monoclonal PCs in 18/25 cases (72.0%), including 2/2 IFE-negative cases (100%). POEMS-flow detected monoclonal PCs with immunophenotypes of CD19- in 17/18 (94.4%). In six cases where post-treatment samples were available, the size of the clones was significantly reduced after the treatment (P = 0.031). POEMS-flow can enhance the identification rate of monoclonal PCs in POEMS syndrome and become a valuable tool for the diagnosis of POEMS syndrome.


Assuntos
Citometria de Fluxo , Síndrome POEMS , Plasmócitos , Síndrome POEMS/diagnóstico , Humanos , Citometria de Fluxo/métodos , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Plasmócitos/metabolismo , Plasmócitos/patologia , Adulto , Imunofenotipagem/métodos , Medula Óssea/patologia
12.
Elife ; 122023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37266576

RESUMO

Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and ß-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.


Assuntos
Mielopoese , Complexo Repressor Polycomb 1 , Animais , Camundongos , Complexo Repressor Polycomb 1/metabolismo , Mielopoese/genética , Histonas , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/metabolismo
13.
Cancer Discov ; 13(1): 216-243, 2023 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-36264161

RESUMO

A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extranodal dissemination, which is associated with inferior clinical outcomes. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate with minimal T-cell costimulation. Additionally, Myd88L252P skewed B cells toward memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B cells of their competitive fitness. By identifying a phenotypically defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients. SIGNIFICANCE: Extranodal lymphomas feature a very poor prognosis. The identification of phenotypically distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diagnosis, patient stratification, and prophylactic interventions. Conceptually, we found that extranodal lymphomas and autoimmune disorders harness overlapping pathogenic trajectories, suggesting these B-cell disorders develop and evolve within a spectrum. See related commentary by Leveille et al. (Blood Cancer Discov 2023;4:8-11). This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Linfócitos B , Linfoma Difuso de Grandes Células B , Humanos , Animais , Camundongos , Idoso , Estudos Prospectivos , Linfoma Difuso de Grandes Células B/patologia , Mutação , Prognóstico
14.
JCI Insight ; 7(20)2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36129760

RESUMO

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.


Assuntos
Mieloma Múltiplo , Síndrome POEMS , Humanos , Síndrome POEMS/diagnóstico , Síndrome POEMS/etiologia , Síndrome POEMS/patologia , Plasmócitos/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Análise de Célula Única , Cadeias lambda de Imunoglobulina/genética , Cadeias lambda de Imunoglobulina/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Células Clonais/patologia , Mieloma Múltiplo/patologia , Aminoácidos/metabolismo
15.
Curr Cancer Drug Targets ; 21(4): 274-282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33413063

RESUMO

Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin B cell lymphoma (NHL), and manifests highly heterogeneous genetic/phenotypic characteristics as well as variable responses to conventional immunochemotherapy. Genetic profiling of DLBCL patients has revealed highly recurrent mutations of epigenetic regulator genes such as CREBBP, KMT2D, EZH2 and TET2. These mutations drive malignant transformation through aberrant epigenetic programming of B-cells and may influence clinical outcomes. These and other chromatin modifier genes also play critical roles in normal B-cells, as they undergo the various phenotypic transitions characteristic of the humoral immune response. Many of these functions have to do with impairing immune surveillance and may critically mediate resistance to immunotherapies. In this review, we describe how epigenetic dysfunction induces lymphomagenesis and discuss ways of implementing precision epigenetic therapies to reverse these immune resistant phenotypes.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias , Epigênese Genética , Heterogeneidade Genética , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Mutação , Proteínas de Neoplasias/classificação , Proteínas de Neoplasias/genética
16.
Front Cell Dev Biol ; 9: 805195, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35071240

RESUMO

B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

17.
Sci Rep ; 11(1): 2074, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483574

RESUMO

The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.


Assuntos
Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Mieloma Múltiplo/patologia , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/metabolismo , Bortezomib/administração & dosagem , Bortezomib/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Quimioterapia Combinada , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Polimerização , Inibidores de Proteassoma/administração & dosagem , Pirazinas/administração & dosagem , Pirazinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Blood Adv ; 3(17): 2537-2549, 2019 09 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.


Assuntos
Carcinogênese/química , Proteínas F-Box/fisiologia , Histona Desmetilases com o Domínio Jumonji/fisiologia , Leucemia de Células T/etiologia , Complexo Repressor Polycomb 1/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Ilhas de CpG , Proteínas F-Box/metabolismo , Histonas , Humanos , Histona Desmetilases com o Domínio Jumonji/deficiência , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Mutação , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Domínios Proteicos , Receptor Notch1/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Ativação Transcricional , Dedos de Zinco
19.
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
20.
Clin J Gastroenterol ; 12(4): 330-335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30903514

RESUMO

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. We report a 27-year-old male patient with Crohn's disease (CD) who developed immunomodulator-associated lymphoproliferative disorder. The patient was diagnosed with CD at the age of 17 and was treated with maintenance therapy including high-dose infliximab and azathioprine. When he was admitted to our hospital with a diagnosis of intestinal obstruction, his abdominal computed tomography findings showed not only colonic wall thickening and narrowing of the descending colon but also multiple liver tumor lesions. His ileus symptom improved with conservative therapy, and a pathological evaluation of the tissue biopsy specimens from the descending colon and liver lesions indicated a morphological diagnosis of EBV-positive diffuse large B-cell lymphoma. This was a case of iatrogenic immunodeficiency-associated lymphoproliferative disorder due to an immunomodulator. The treatment was initiated with chemotherapy, but he died of disease progression 10 months after the diagnosis of lymphoma. Although cases of lymphoproliferative disorder due to treatment modalities used for CD are rare in Japan, an increase in the risk of lymphoproliferative diseases should be considered in patients with CD treated with immunomodulatory agents.


Assuntos
Doença de Crohn/tratamento farmacológico , Infecções por Vírus Epstein-Barr/complicações , Imunossupressores/efeitos adversos , Linfoma Difuso de Grandes Células B/virologia , Adulto , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Colonoscopia , Doença de Crohn/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Evolução Fatal , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Tomografia Computadorizada por Raios X , Úlcera/imunologia , Úlcera/virologia
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