RESUMO
An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and -independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C-C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.
Assuntos
Lenalidomida/farmacologia , Mieloma Múltiplo/imunologia , Células Supressoras Mieloides/imunologia , Talidomida/análogos & derivados , Linhagem Celular Tumoral , Quimiocina CCL5/imunologia , Técnicas de Cocultura , Humanos , Fatores Reguladores de Interferon/imunologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Células Supressoras Mieloides/patologia , Proteínas de Neoplasias/imunologia , Talidomida/farmacologiaRESUMO
Despite the recent therapeutic progress, the prognoses of diffuse large B-cell lymphomas (DLBCLs) that concomitantly overexpress c-MYC and BCL2, i.e., double hit lymphoma (DHL) and double expressing lymphoma (DEL), remain poor. This study examined triple targeting of c-MYC, BCL2 and the B-cell receptor (BCR) signaling pathway for DHL and DEL. We first used AZD5153, a novel bivalent inhibitor for bromodomain-containing 4 (BRD4), in DHL- and DEL-derived cell lines, because BRD4 regulates disease type-oriented key molecules for oncogenesis. AZD5153 was more effective than conventional monovalent BRD4 inhibitors, JQ1 and I-BET151, in inhibiting cell proliferation of a DHL-derived cell line and two DEL-derived cell lines, with at least 10-fold lower half growth inhibitory concentrations. AZD5153 caused G1/S cell cycle blockade, while the apoptosis-inducing effect was relatively modest. At the molecular level, AZD5153 was potent in downregulating various molecules for oncogenesis, such as c-MYC, AKT2 and MAP3K; those involved in the BCR signaling pathway, such as CD19, BLNK and CD79B; and those associated with B-cell development, such as IKZF1, IKZF3, PAX5, POU2AF1 and EBF1. In contrast, AZD5153 did not decrease anti-apoptotic BCL2 proteins, and did not activate pro-apoptotic BH3-only proteins, except BAD. To augment cell death induction, we added a novel BH3-mimicking BCL2 inhibitor AZD4320 to AZD5153, and found that these two agents had a mostly synergistic antitumor effect by increasing cells undergoing apoptosis in all three cell lines. These results provide a rationale for dual targeting of BRD4 and BCL2 using AZD5153 and AZD4320 as a therapeutic strategy against DHL and DEL.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Linfoma de Células B/tratamento farmacológico , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Pirazóis , Piridazinas , Células Tumorais CultivadasRESUMO
To identify risk factors for varicella zoster virus (VZV) infection and postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT), we conducted a retrospective chart review of 163 consecutive patients who underwent HCT between November 2004 and July 2014. Overall, the male/female (M/F) ratio was 80/83, median age at HCT was 54 (range 15-69) years, and autologous/allogeneic HCT (auto/allo-HCT) ratio was 71/92. Forty-four patients [M/F, 25/19; median age, 57 (range: 16-68) years; auto/allo-HCT, 26/18] developed VZV infection after HCT. All cases were successfully treated with acyclovir (ACV) or valacyclovir, and there was no VZV-related death. Nine (20%) of the 44 patients [M/F, 5/4; median age, 58 (range: 21-63) years; auto/allo-HCT, 7/2] developed PHN after resolution of zoster. Multivariate ordered logistic analysis identified receiving immunosuppressive therapy at the cessation of ACV [odds ratio (OR) = 74.53; 95% confidence interval (CI) = 6.99-794.32; P = 0.0004] as a risk factor for VZV infection and PHN in allo-HCT recipients. However, in auto-HCT recipients, only advanced age was identified as a risk factor (OR = 1.06, 95% CI = 1.002-1.127, P = 0.0429). Our findings indicate receiving immunosuppressive therapy at the cessation of ACV is a significant risk factor for allo-HCT recipients, while advanced age is a significant risk factor for auto-HCT recipients.
Assuntos
Varicela/diagnóstico , Varicela/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 3 , Neuralgia Pós-Herpética/diagnóstico , Neuralgia Pós-Herpética/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
The deleted in colorectal carcinoma (DCC) gene at 18q21 encodes a netrin-1 receptor, a tumor suppressor that prevents cell growth. While allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies, including leukemias and malignant lymphomas, its involvement has not been evaluated in multiple myeloma (MM), a plasma cell malignancy characterized by complex and heterogenous molecular abnormalities. We here show that 10 of 11 human myeloma-derived cell lines (HMCLs) expressed non-translated aberrant DCC transcriptional variants, in which exon 2 fuses with intron 1 instead of exon 1 (mt.DCC). Among them, two co-expressed wild type transcripts (wt.DCC), while eight co-expressed the splicing variant (sv.DCC) lacking exon 1. The remaining HMCL expressed only sv.DCC. In addition, analyses revealed that there were two types of mt.DCC that differed in their fusion of intron 1 with exon 2. In patient-derived samples from 30 MM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients, wt.DCC was expressed in 53% of MM, but not in MGUS, while 23% of MM and 75% of MGUS expressed only sv.DCC. Considering that 25% of MGUS, 57% of MM, and 91% HMCLs expressed mt.DCC, our results suggest that the acquisition of mt.DCC might be a secondary genetic change in plasma cell dyscrasia.
Assuntos
Genes Supressores de Tumor , Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biomarcadores Tumorais/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Cromossomos Humanos Par 18/genética , Receptor DCC , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Regulação para Baixo , Éxons , Humanos , Íntrons , Perda de Heterozigosidade , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Superfície Celular/metabolismo , Proteína Smad4/metabolismo , Sindecana-1/genética , Fator de Transcrição 4 , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
The monocytic leukemia zinc finger protein KAT6A (formerly MOZ) gene is recurrently rearranged by chromosomal translocations in acute myeloid leukemia (AML). KAT6A is known to be fused to several genes, all of which have histone acetyltransferase (HAT) activity and interact with a number of transcription factors as a transcriptional coactivator. The present study shows that the leucine twenty homeobox (LEUTX) gene on 19q13 is fused to the KAT6A gene on 8p11 in a therapy-related AML with t(8;19)(p11;q13) using the cDNA bubble PCR method. The fusion transcripts contained 83 nucleotides upstream of the first ATG of LEUTX and are presumed to create in-frame fusion proteins. LEUTX is known to have a homeobox domain. Expression of the LEUTX gene was only detected in placenta RNA by RT-PCR, but not in any tissues by Northern blot analysis. The putative LEUTX protein does not contain any HAT domain, and this is the first study to report that KAT6A can fuse to the homeobox gene. The current study, with identification of a new partner gene to KAT6A in a therapy-related AML, does not elucidate the mechanisms of leukemogenesis in KAT6A-related AML but describes a new gene with a different putative function.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 8/genética , Histona Acetiltransferases/genética , Proteínas de Homeodomínio/genética , Leucemia Mieloide Aguda/genética , Sequência de Aminoácidos , Sequência de Bases , Evolução Fatal , Fusão Gênica , Genes Homeobox , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Dados de Sequência Molecular , Translocação GenéticaAssuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/fisiologia , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Infecções por Vírus Epstein-Barr/virologia , Humanos , Mesilato de Imatinib/uso terapêutico , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Esplenomegalia , Tomografia Computadorizada por Raios X , Vincristina/efeitos adversos , Vincristina/uso terapêuticoAssuntos
Linfoma Intraocular/tratamento farmacológico , Células Matadoras Naturais/patologia , Corpo Vítreo/patologia , Idoso , Asparaginase/administração & dosagem , Terapia Combinada , Dexametasona/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Injeções Intraoculares , Linfoma Intraocular/diagnóstico , Linfoma Intraocular/patologia , Linfoma Intraocular/radioterapia , Metotrexato/administração & dosagem , Radioterapia Adjuvante/métodos , Indução de RemissãoRESUMO
Bone marrow (BM) microenvironment (BMME) constitutes the sanctuary for leukemic cells. In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the ß-gal-binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migration to HS-5-derived soluble factors in CML cell lines independently of Bcr-Abl tyrosine kinase. The conditioned medium from Gal-3-overexpressing CML cells promoted in vitro cell proliferation of CML cells and HS-5 cells more than did the conditioned medium from parental cells. Moreover, the in vivo study in a mice transplantation model showed that Gal-3 overexpression promoted the long-term BM lodgment of CML cells. These results demonstrate that leukemia microenvironment-specific Gal-3 expression supports molecular signaling pathways for disease maintenance in BM and resistance to therapy in CML. They also suggest that Gal-3 may be a candidate therapeutic target to help overcome BMME-mediated therapeutic resistance.
Assuntos
Galectina 3/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Animais , Medula Óssea/patologia , Linhagem Celular Tumoral , Proliferação de Células , Meios de Cultivo Condicionados , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Biológicos , Transplante de Neoplasias , Transdução de Sinais , Transplante Heterólogo , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologiaRESUMO
PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia (CML), however, the cell killing mechanism underlying its anti-leukemic activity has remained to be verified. We investigated the precise mechanisms underlying the apoptosis induction by FTY720, especially focusing on the roles of BH3-only proteins, and the therapeutic potency of FTY720 for CML. Enforced expression of either BCL2 or the dominant-negative protein of FADD (FADD.DN) partly protected CML cells from apoptosis by FTY720, indicating the involvement of both cell extrinsic and intrinsic apoptosis pathways. FTY720 activates pro-apoptotic BH3-only proteins: BIM, which is essential for apoptosis by BCR-ABL1 tyrosine kinase inhibitors (TKIs), and BID, which accelerates the extrinsic apoptosis pathway. Gene knockdown of either BIM or BID partly protected K562 cells from apoptosis by FTY720, but the extent of cell protection was not as much as that by overexpression of either BCL2 or FADD.DN. Moreover, knockdown of both BIM and BID did not provide additional protection compared with knockdown of only BIM or BID, indicating that BIM and BID complement each other in apoptosis by FTY720, especially when either is functionally impaired. FTY720 can overcome TKI resistance caused by ABL kinase domain mutations, dysfunction of BIM resulting from gene deletion polymorphism, and galectin-3 overexpression. In addition, ABT-263, a BH3-mimetic, significantly augmented cell death induction by FTY720 both in TKI-sensitive and -resistant leukemic cells. These results provide the rationale that FTY720, with its unique effects on BIM and BID, could lead to new therapeutic strategies for CML.
Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Membrana/genética , Propilenoglicóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Esfingosina/análogos & derivados , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/antagonistas & inibidores , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Cloridrato de Fingolimode , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Mutação , Cultura Primária de Células , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Esfingosina/farmacologia , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
High-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT) has long been one of the standards of care for younger patients with multiple myeloma (MM). Cyclophosphamide (CY) plus granulocyte colony-stimulating factor (G-CSF) has been the conventional preparation for hematopoietic progenitor cell (HPC) mobilization, although the optimal dosage of CY in this setting has not yet been clearly defined. This study investigated the efficacy and safety of low-dose (LD-)CY (1.5 g/m(2)) plus G-CSF for conditioning for HPC apheresis harvest (HPC-A) in 18 MM patients, and compared it with a regimen consisting of intermediate-dose (ID)-CY (4 g/m(2)) plus G-CSF for 13 MM patients. Eleven patients in the former and six in the latter were treated with bortezomib (BTZ) during the induction therapy. Both regimens were comparably effective in terms of CD34(+) cell yields, while adverse events, such as leukopenia, thrombocytopenia, and febrile neutropenia, occurred significantly less frequently in the LD-CY cohort. All patients in LD-CY cohort started and completed their apheresis on day 7 or 8, whereas for the ID-CY cohort the day of first apheresis varied widely from day 8 to 15. These findings indicate that the LD-CY regimen is as effective as ID-CY for HPC mobilization, while the former is clearly more practicable and convenient than the ID-CY regimen for patients with MM.
Assuntos
Ciclofosfamida/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Mieloma Múltiplo/terapia , Adulto , Idoso , Antígenos CD34/metabolismo , Remoção de Componentes Sanguíneos , Ácidos Borônicos/administração & dosagem , Bortezomib , Esquema de Medicação , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Plasmocitoma/terapia , Pirazinas/administração & dosagem , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Transplante Autólogo , Resultado do TratamentoRESUMO
The mammalian homeobox transcription factor CDX2 has key roles in intestinal development and differentiation. Heterozygous Cdx2 mice develop one or two benign hamartomas in the proximal colon, whereas heterozygous Apc(Delta716) mice develop numerous adenomatous polyps, mostly in the small intestine. Here we show that the colonic polyp number is about six times higher in Apc+/Delta716 Cdx2+/- compound mutant mice. Levels of both APC and CDX2 were significantly lower in the distal colon, which caused high anaphase bridge index (ABI) associated with a higher frequency of loss of heterozygosity (LOH) at Apc. In cultured rat intestinal epithelial and human colon cancer cell lines, suppression of CDX2 by antisense RNA caused marked increases in ABI and chromosomal aberrations. This was mediated by stimulation of the mTOR pathway, causing translational deregulation and G1-S acceleration, associated with low levels of p27 and activation of cyclin E-Cdk2. We obtained similar results in the colonic mucosa of Apc+/Delta716) Cdx2+/- compound mutant mice. Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells. High ABI in all cell lines was suppressed by mTOR inhibitors LY294002 and rapamycin. These results suggest that reduced expression of CDX2 is important in colon tumorigenesis through mTOR-mediated chromosomal instability.
Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Instabilidade Cromossômica/genética , Proteínas de Homeodomínio/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Proteína da Polipose Adenomatosa do Colo/deficiência , Proteína da Polipose Adenomatosa do Colo/genética , Anáfase , Animais , Bromodesoxiuridina , Fator de Transcrição CDX2 , Sobrevivência Celular , Células Cultivadas , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fase G1 , Heterozigoto , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/genética , Humanos , Marcação In Situ das Extremidades Cortadas , Perda de Heterozigosidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , RNA Antissenso/farmacologia , Ratos , Fase S , Serina-Treonina Quinases TOR , TransativadoresRESUMO
Angioimmunoblastic T cell lymphoma (AITL) is a rare subtype of T cell non-Hodgkin lymphoma. The standard therapeutic strategy for AITL has not yet been established, and its prognosis remains poor. This report concerns the effect of cyclosporin A (CsA) on chemotherapy-refractory AITL. A 68-year-old female with AITL with systemic symptoms, such as high fever, skin rash and generalized lymphadenopathy, was initially treated with conventional cytotoxic chemotherapies using alkylators, anthracyclines and corticosteroids, which failed to induce remission. However, CsA (4 mg/kg/day) plus dexamethasone treatment resulted in a dramatic regression of the tumors and amelioration of systemic symptoms and induced complete remission (CR) within 2 weeks. Currently, the patient's CR has continued for more than 18 months with CsA maintenance therapy. Our experience and previously reported findings suggest that CsA may constitute an alternative treatment option for AITL, even though the use of conventional cytotoxic chemotherapy continues to be the first-line therapy on an empirical basis.
Assuntos
Ciclosporina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunossupressores/administração & dosagem , Linfoma de Células T/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Humanos , Linfoma de Células T/patologiaRESUMO
OBJECTIVE: The incorporation of rituximab in immunochemotherapy has improved treatment outcomes for diffuse large B-cell lymphoma, but the prognosis for some diffuse large B-cell lymphomas remains dismal. Identification of adverse prognostic subgroups is essential for the choice of appropriate therapeutic strategy. METHODS: We retrospectively investigated the impact of so-called 'double-hit' cytogenetic abnormalities, i.e. cytogenetic abnormalities involving c-MYC co-existing with other poor prognostic cytogenetic abnormalities involving BCL2, BCL6 or BACH2, on treatment outcomes for 93 consecutive diffuse large B-cell lymphoma patients. RESULTS: According to the revised international prognostic index, no patients were cytogenetically diagnosed with double-hit lymphomas in the 'very good' risk group or in the 'good' risk group, while 5 of 33 patients had double-hit lymphomas in the 'poor' risk group. All the double-hit lymphoma patients possessed both nodal and extranodal involvement. The overall complete response rate was 89.3%, overall survival 87.1% and progression-free survival 75.8% over 2 years (median observation period: 644 days). The complete response rates were 93.2% for the non-double-hit lymphoma patients and 40.0% for the double-hit lymphoma patients. Significantly longer progression-free survival and overall survival were observed for the 'very good' and the 'good' risk patients than for the 'poor' risk patients. Moreover, the progression-free survival of double-hit lymphoma was significantly shorter than that of the non-double-hit lymphoma 'poor' risk patients (P = 0.016). In addition, the overall survival of the double-hit lymphoma patients also tended to be shorter than that of the non-double-hit lymphoma 'poor' risk group. CONCLUSIONS: The diagnosis of double-hit lymphoma can help discriminate a subgroup of highly aggressive diffuse large B-cell lymphomas and indicate the need for the development of novel therapeutic strategies for double-hit lymphoma.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Fatores de Transcrição de Zíper de Leucina Básica/genética , Aberrações Cromossômicas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Genes myc/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Estudos Retrospectivos , Rituximab , Resultado do TratamentoRESUMO
In B-cell malignancies, genes implicated in B-cell differentiation, germinal center formation, apoptosis, and cell cycle regulation are juxtaposed to immunoglobulin loci through chromosomal translocations. In this study, we identified the BTB and CNC homology 2 (BACH2) gene as a novel translocation partner of the immunoglobulin heavy chain (IGH) locus in a patient with IGH-MYC-positive, highly aggressive B-cell lymphoma/leukemia carrying der(14)t(8;14) and del(6)(q15). Fluorescence in situ hybridization analysis using an IGH/MYC probe detected an IGH-MYC fusion signal on der(14) and IGH signal on del(6). Genome copy number analysis showed a deletion in the 6q15-25 region and a centromeric breakpoint within the BACH2 gene. cDNA bubble polymerase chain reaction using BACH2 primers revealed that the first exon of Cδ was fused to the 5'-untranslated region of BACH2 exon 2. The Cδ-BACH2 fusion transcript consisted of exon 1 of Cδ and exons 2 to 9 of BACH2, encompassing the entire BACH2 coding region, and the BACH2 was highly expressed in this patient. These results indicate that Cδ-BACH2 fusion may cause constitutive activation of BACH2. Although additional screening of 47 samples of B-cell non-Hodgkin's lymphoma (B-NHL) patients and 29 cell lines derived from B-cell malignancies by double-color fluorescence in situ hybridization analysis detected a split signal with deletion of centromeric region of BACH2 only in a patient with follicular lymphoma, BACH2 was highly expressed in lymphoma cells of the patient and B-NHL cell lines with IGH-MYC translocation. These findings suggest that BACH2 plays a critical role in B-cell lymphomagenesis, especially related to IGH-MYC translocation in some way.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Cadeias delta de Imunoglobulina/genética , Linfoma de Células B/genética , Translocação Genética , Idoso , Linfócitos B/metabolismo , Sequência de Bases , Pontos de Quebra do Cromossomo , DNA de Neoplasias/genética , Regulação Leucêmica da Expressão Gênica , Fusão Gênica , Genes myc , Humanos , Hibridização in Situ Fluorescente , Leucemia/genética , Linfoma de Células B/patologia , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNARESUMO
BACKGROUND: Combinatory strategies with carfilzomib (CFZ), a second-generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting. AIMS: To evaluate the real-world efficacy and safety of CFZ-based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian patients, we conducted a multicenter pilot prospective observational study in the Kyoto Clinical Hematology Study Group. METHODS AND RESULTS: All 50 patients with RRMM enrolled in this study were treated with CFZ-based treatments between 2017 and 2019. KRD and KD were administered to 31 and 19 patients, respectively. The overall response rates (ORRs) were 80.6% with KRD and 73.7% with KD. Two-year progression-free survival (PFS) and overall survival (OS) were 58.5% and 79.7% with KRD, and 23.1% and 52.6% with KD. By multivariate analysis, refractoriness to BTZ and to LEN were identified as independent unfavorable factors for both PFS and OS. The common non-hematologic AEs included hypertension (42.0%), fever (24.0%), fatigue (24.0%), and infection (16.0%). No serious heart failure was observed. This study is registered as UMIN000025108. CONCLUSION: This study suggests the need of the development of novel CFZ-containing strategy which can overcome the refractoriness to BTZ and/or LEN, while both KRD and KD were shown to be mostly feasible in Asian patients in a daily practice setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Feminino , Humanos , Japão , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Projetos Piloto , Prognóstico , Estudos ProspectivosRESUMO
The hypomethylating agent azacitidine (AZA) significantly extends overall survival (OS) in patients with higher risk myelodysplastic syndromes (MDS), when compared with other conventional care regimens, including supportive care and low-dose and intensive chemotherapy. However, the effects of 5- and 7-day treatment schedules of AZA (AZA-5 and AZA-7, respectively) on the OS of MDS patients had not been compared prospectively. We started a phase 3 trial comparing the effects of AZA-7 and AZA-5 on MDS patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T). However, this trial was prematurely terminated because of poor recruitment. Using all data, there was no significant difference in the OS of patients between AZA-7 (92 patients) and AZA-5 (95 patients), with the 2-year OS rates of AZA-7 and AZA-5 at 36.4% and 25.8%, respectively (P = 0.293). Adverse event profiles were similar between the two groups. Interestingly, data of the centrally diagnosed RAEB and RAEB-T cases showed that AZA-7 significantly prolonged the time to leukemia transformation compared with AZA-5 (P = 0.022), confirmed by multivariate analysis. Although this trial could not provide definite evidence, the results support the use of AZA-7 for RAEB and RAEB-T. (UMIN Clinical Trials Registry UMIN000009633).
Assuntos
Anemia Refratária com Excesso de Blastos , Azacitidina , Síndromes Mielodisplásicas , Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Humanos , Síndromes Mielodisplásicas/tratamento farmacológicoRESUMO
Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a rare subtype of non-Hodgkin lymphoma for which a definitive therapeutic strategy has not been established yet. We report a case of chemotherapy-resistant SPTL with hemophagocytic syndrome (HPS) which was successfully treated with cyclosporine A (CsA) plus methylprednisolone (mPSL), and also reviewed 11 SPTL cases treated with CsA, previously reported in the literature. Our patient was a 38-year-old female with SPTL. The disease progressed despite conventional chemotherapy using cytotoxic agents including alkylators, anthracyclins or purine analogues, and, after 2 months of chemotherapy, was eventually complicated by HPS and disseminated intravascular coagulation (DIC). CsA (4 mg/kg/day) plus mPSL treatment dramatically improved HPS with DIC, reduced subcutaneous tumors within 2 weeks, and finally induced complete remission (CR) after 3 months. Currently, the patient has maintained CR while being treated with CsA for 12 months. In addition to our case, 9 of 11 SPTL cases were successfully treated with CsA, and 8 were induced to CR. Time to first response to CsA was within 2 weeks in most cases, regardless of prior treatment or the co-occurrence of HPS. Our case and this first comprehensive review on CsA for SPTL suggest that CsA may constitute a candidate treatment strategy for SPTL.
Assuntos
Ciclosporina/uso terapêutico , Linfo-Histiocitose Hemofagocítica/complicações , Adulto , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma de Células T/complicações , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/tratamento farmacológico , Paniculite/complicações , Paniculite/diagnóstico por imagem , Paniculite/tratamento farmacológico , Tomografia por Emissão de PósitronsRESUMO
Infection with human parvovirus B19 (PVB19) induces acquired pure red cell aplasia (PRCA). Chronic hemolytic anemia is well known as an underlying condition. However, additional factors have been recognized to accompany parvoviral PRCA; however, there are only limited reports on iron-deficiency anemia (IDA) and rituximab-induced B-cell dysfunction. We report two patients with PVB19-associated PRCA confirmed by positivity of viral DNA. Although they had no chronic hemolysis, patient 1 had IDA, and patient 2 had remitted small-lymphocytic lymphoma treated with rituximab-containing chemotherapy. Absence of reticulocytes in peripheral blood and marked depletion of erythroid precursors in bone marrow were observed both. Whereas patient 1 received only symptomatic therapy because anemia was not severe, patient 2 was treated with steroids, as PRCA etiology was at first uncertain, and immunological PRCA was not excluded. Both showed rapid increase of reticulocyte counts and recovery from anemia. Although immunoglobulin is considered effective for parvoviral PRCA, notable adverse reactions have been reported. When anemic symptom is not severe, reticulocyte observation only is recommended. The effects of steroids should also be re-evaluated. Optimal treatment according to disease severity remains to be established.
Assuntos
Anemia Ferropriva/complicações , Leucemia Linfocítica Crônica de Células B/complicações , Aplasia Pura de Série Vermelha/virologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , DNA Viral/análise , DNA Viral/genética , Feminino , Hemólise , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , Pessoa de Meia-Idade , Infecções por Parvoviridae/virologia , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/isolamento & purificação , RituximabRESUMO
For this study, we investigated comprehensive expression of conjoined genes (CGs) in non-Hodgkin B-cell lymphoma (B-NHL) cell line KPUM-UH1 by using paired-end RNA sequencing. Furthermore, we analyzed the expression of these transcripts in an additional 21 cell lines, 37 primary samples of various malignancies and peripheral blood mononuclear cells of four normal individuals. Seventeen CGs were detected in KPUM-UH1: CTBS-GNG5, SRP9-EPHX1, RMND5A-ANAPC, OTX1-EHBP1, ATF2-CHN1, PRKAA1-TTC33, LARP1-MRPL22, LOC105379697-BAK1, TIAM2-SCAF8, SPAG1-VPS13B, WBP1L-CNNM2, NARS2-GAB2, CTSC-RAB38, VAMP1-CD27-AS1, LRRC37A2-NSF, UBA2-WTIP and ZNF600-ZNF611. To our knowledge, 10 of these genes have not been previously reported. The various characteristics of the CGs included in- and out-of-frame fusions, chimeras involving non-coding RNA and transcript variants. A finding of note was that LARP1-MRPL2 was characterized as in-frame fusion and was recurrently expressed in B-NHL samples. In this study, variety of CGs was expressed both in malignant and normal cells, some of which might be specific to lymphoma.
Assuntos
Linfoma de Células B/genética , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Sequência de Bases , Linhagem Celular Tumoral , Dosagem de Genes , Humanos , Análise de Sequência de RNA , Células Tumorais CultivadasRESUMO
Multiple myeloma (MM) is cytogenetically, genetically and molecularly heterogenous even among subclones in one patient, therefore, it is essential to identify both frequent and patient-specific drivers of molecular abnormality. Following previous molecular investigations, we in this study investigated the expression patterns and function of the Ewing sarcoma breakpoint region 1 (EWSR1) gene in MM. The EWSR1 transcriptional level in CD138-positive myeloma cells was higher in 36.4% of monoclonal gammopathy of undetermined significance, in 67.4% of MM patients compared with normal plasma cells, and significantly higher in ten human myeloma-derived cell lines (HMCLs) examined. EWSR1 gene knockdown caused growth inhibition with an increase of apoptotic cells in NCI-H929 and KMS-12-BM cells. Gene expression profiling using microarray analysis suggested EWSR1 gene knockdown caused transcriptional modulation of several genes associated with processes such as cell proliferation, cell motility, cell metabolism, and gene expression. Of particular, EWSR1 gene knockdown caused upregulation of let-7c and downregulation of its known targets K-RAS and AKT. Finally, our analysis using community database suggested that high EWSR1 expression positively associates with poor prognosis and advanced disease stage in MM. These findings suggest that EWSR1 overexpression is a pro-oncogenic molecular abnormality that may participate in MM progression.