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1.
Zhonghua Bing Li Xue Za Zhi ; 49(11): 1136-1141, 2020 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-33152818

RESUMO

Objective: To investigate the relationship between six common cytogenetic abnormalities and bone marrow pathomorphology in multiple myeloma (MM). Methods: Bone marrow biopsy was performed on 151 newly-diagnosed MM patients. Meanwhile, myeloma cells were enriched by CD138 immunomagnetic beads, and then lq+, 13q-, 17p-, t(4;14), t (11;14), t (14;16) and other common genetic abnormalities were detected using interphase fluorescence in situ hybridization (FISH). The relationship between different genetic abnormalities and biopsy morphology was compared. Results: Of the 151 patients, 15 had extramedullary infiltration (9.9%). The rate of cytogenetic abnormalities was 76.2% (115/151), of which 1q+ accounted for 49.7% (75/151), 13q-39.1% (59/151), 17p-8.6% (13/151), t(4;14) 21.2% (32/151), t(11;14) 19.2% (29/151), and t(14;16) 2.0% (3/151). The proliferation patterns of MM plasma cells were nodular (48.3%, 73/151), interstitial (33.8%, 51/151) and diffuse (17.9%, 27/151). The morphology of plasma cells was mainly mature type (58.3%, 88/151), followed by juvenile type (20.5%, 31/151), intermediate type (15.9%, 24/151) and plasmacyte type (5.3%, 8/151). According to the mSMART risk stratification system, the proliferation pattern of myeloma cells in the high-risk group was mainly diffuse type, and the morphology was mainly immature and plasmacyte type. In the middle-risk group, mature type myeloma cells were mainly nodular proliferating. In the low-risk and negative group, mature type myeloma cells were mainly interstitial proliferating. There was no difference in the probability of different proliferation modes of intermediate type plasma cells in each group. Conclusions: The proliferation pattern and morphology of plasma cells in bone marrow biopsy combined with cytogenetic markers can more accurately predict the severity and prognosis of MM.


Assuntos
Mieloma Múltiplo , Adolescente , Medula Óssea , Aberrações Cromossômicas , Humanos , Hibridização in Situ Fluorescente , Mieloma Múltiplo/genética , Plasmócitos , Prognóstico
2.
Lancet Oncol ; 21(11): 1478-1488, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33128873

RESUMO

BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.


Assuntos
Cumarínicos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Adulto , Idoso , Cumarínicos/efeitos adversos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Quinases raf/genética , Proteínas ras/genética
3.
Anticancer Res ; 40(10): 5437-5443, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988865

RESUMO

BACKGROUND: Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A (VEGFA), and has been reported to be overexpressed in several malignancies. Since angiogenesis plays an important role in pathogenesis of multiple myeloma (MM) and the role of NRP1 in MM has not been studied yet, we characterized the expression of NRP1 in this disease. MATERIALS AND METHODS: The expression level of NRP1 was measured in 140 patients newly diagnosed with MM and 28 healthy controls by flow cytometry and quantitative reverse transcriptase polymerase chain reaction. RESULTS: Expression of NRP1 was significantly reduced on plasma cells (median=2.05%) compared to that on B-cells (median=10.05%, p<0.0001) in bone marrow of patients with MM. In MM, the expression of NRP1 was high on plasmacytoid dendritic cells (median=85.85%) and low on regulatory T-cells (median=0.6%). CONCLUSION: In MM, NRP1 is regulated differentially as compared to other B-cell malignancies at both the RNA and protein level.


Assuntos
Mieloma Múltiplo/genética , Neovascularização Patológica/genética , Neuropilina-1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Linfócitos B/metabolismo , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neuropilina-1/sangue , Transdução de Sinais/genética
4.
Anticancer Res ; 40(9): 4979-4987, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878786

RESUMO

BACKGROUND/AIM: Multiple myeloma is a highly heterogeneous disease of clonal plasma cells. Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their precise mechanisms of actions are not well understood. MATERIALS AND METHODS: Cell-cycle regulation and pro-apoptotic effects of two histone deacetylase inhibitors, suberohydroxamic acid (SAHA) and suberoylanilide hydroxamic acid (SBHA), were analyzed in multiple myeloma cell lines RPMI8226 and U266 with differing TP53 status using gene-expression analysis. RESULTS: Enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21WAF/CIP1) detected in the TP53-deleted U266 cell line after SAHA treatment indicates the P53-independent mode of transcriptional activation of CDKN1A gene. In contrast, CDKN1A gene expression was significantly increased by both SBHA and SAHA treatment of TP53-mutated RPMI8226 cells. CONCLUSION: SAHA appears to be a potentially effective pro-apoptotic and anticancer drug with universal application in the treatment of heterogeneous populations of multiple myeloma cells.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Mieloma Múltiplo/patologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteína Supressora de Tumor p53/genética
5.
Ann Hematol ; 99(10): 2351-2356, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32865607

RESUMO

Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2-9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42-83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21-33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Neutropenia Febril/induzido quimicamente , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Intervalo Livre de Progressão , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1087-1091, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924107

RESUMO

OBJECTIVE: To detect chromosomal aberrations by using cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization (cIg-FISH), and to explore the correlation of del(17p13) with clinical characteristics, drug response and prognosis among patients with newly diagnosed multiple myeloma (NDMM). METHODS: Clinical data of 198 cases of NDMM was collected. cIg-FISH and a specific probe (TP53) were used to detect karyotypic abnormalities in bone marrow samples derived from the patients. Correlation between karyotypic abnormalities and clinical data was analyzed. RESULTS: Nineteen of the 198 patients (9.6%) were found to have a karyotype involving del(17p13). The overall survival (OS) and progression-free survival (PFS) for patients with or without del(17p13) was significantly different (P<0.01). No significant difference was found in OS and PFS between patients carrying a del(17p13) on bortezomib and non-bortezomib regimen (OS: P = 0.873; PFS: P = 0.610). CONCLUSION: cIg-FISH is a simple and convenient method for the detection of karyotypic anomalies in multiple myeloma. Del(17p13) is an indicator for poor prognosis for multiple myeloma patients. Bortezomib cannot improve the survival disadvantage of del(17p13).


Assuntos
Deleção Cromossômica , Imunofluorescência , Mieloma Múltiplo , Cromossomos Humanos Par 17 , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Prognóstico
7.
Proc Natl Acad Sci U S A ; 117(33): 20004-20014, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747568

RESUMO

KRAS, NRAS, and BRAF mutations which activate p44/42 mitogen-activated protein kinase (MAPK) signaling are found in half of myeloma patients and contribute to proteasome inhibitor (PI) resistance, but the underlying mechanisms are not fully understood. We established myeloma cell lines expressing wild-type (WT), constitutively active (CA) (G12V/G13D/Q61H), or dominant-negative (DN) (S17N)-KRAS and -NRAS, or BRAF-V600E. Cells expressing CA mutants showed increased proteasome maturation protein (POMP) and nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression. This correlated with an increase in catalytically active proteasome subunit ß (PSMB)-8, PSMB9, and PSMB10, which occurred in an ETS transcription factor-dependent manner. Proteasome chymotrypsin-like, trypsin-like, and caspase-like activities were increased, and this enhanced capacity reduced PI sensitivity, while DN-KRAS and DN-NRAS did the opposite. Pharmacologic RAF or MAPK kinase (MEK) inhibitors decreased proteasome activity, and sensitized myeloma cells to PIs. CA-KRAS, CA-NRAS, and CA-BRAF down-regulated expression of endoplasmic reticulum (ER) stress proteins, and reduced unfolded protein response activation, while DN mutations increased both. Finally, a bortezomib (BTZ)/MEK inhibitor combination showed enhanced activity in vivo specifically in CA-NRAS models. Taken together, the data support the hypothesis that activating MAPK pathway mutations enhance PI resistance by increasing proteasome capacity, and provide a rationale for targeting such patients with PI/RAF or PI/MEK inhibitor combinations. Moreover, they argue these mutations promote myeloma survival by reducing cellular stress, thereby distancing plasma cells from the apoptotic threshold, potentially explaining their high frequency in myeloma.


Assuntos
Estresse do Retículo Endoplasmático , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/metabolismo , Mieloma Múltiplo/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/fisiopatologia , Mutação , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
Nat Commun ; 11(1): 3617, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680998

RESUMO

Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Evolução Clonal/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Mutação/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Análise de Célula Única , Análise Espaço-Temporal , Transplante Autólogo/efeitos adversos , Sequenciamento Completo do Genoma
9.
Life Sci ; 257: 118088, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663573

RESUMO

AIMS: Bone marrow stromal cells (BMSCs) have been reported to interact with multiple myeloma (MM) and exert a vital function of the survival of MM cells. Heme oxygenase-1 (HO-1), a cytoprotective enzyme, has the potential to become a hematological malignancies targeted gene. This study aimed to investigate the role of HO-1 in MM resistance of BMSCs and its possible mechanisms. MAIN METHODS: In this study, the expression of related proteins was detected by RT-qPCR and Western blot. HO-1 expression was regulated by lentivirus transfection. Cell viability and apoptosis were detected by Flow cytometry and CCK-8. Cytokine secretion was assayed by ELISA. The survival and carcinogenic abilities was detected by clone formation assay. KEY FINDINGS: HO-1 expression in the BMSCs of stage III MM patients was substantially increased, compared with that of healthy donors and stage I/II patients. The results of co-culture of BMSCs and MM cells indicated that, the upregulated HO-1 inhibited the apoptosis of co-cultured MM cells, while downregulated HO-1 promoted the chemosensitivity of co-cultured MM cells, moreover, the upregulated HO-1 in BMSCs increased the colony-formation ability of MM cells. This protective capability may be regulated by CXCL12/CXCR4 signaling. High HO-1 expression in BMSCs can promote the phosphorylation of the JAK2/STAT3 pathway, thereby increasing secretion of SDF-1 in BMSCs and activating CXCL12/CXCR4 signaling. In addition, direct contact between BMSCs and MM cells may cause drug resistance. SIGNIFICANCE: These results indicated that the regulation of HO-1 in BMSCs may be a new effective method of MM therapy.


Assuntos
Antineoplásicos/farmacologia , Heme Oxigenase-1/genética , Células-Tronco Mesenquimais/citologia , Mieloma Múltiplo/patologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Estudos de Casos e Controles , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Estadiamento de Neoplasias , Fator de Transcrição STAT3/metabolismo
10.
Ann Hematol ; 99(10): 2231-2242, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621182

RESUMO

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hematológicas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Autorrenovação Celular/genética , Genes myc , Hematopoese/genética , Humanos , Leucemia/genética , Linfócitos/metabolismo , Linfócitos/patologia , Linfoma/genética , Mieloma Múltiplo/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Nicho de Células-Tronco
13.
Life Sci ; 256: 117971, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553925

RESUMO

AIMS: Multiple myeloma (MM) was recently reported to rely on increased oxidative phosphorylation (OXPHOS) for survival, providing a potential opportunity for MM therapy. Herein, we aimed to propose a novel targeted drug for MM treatment, followed by the exploration of reason for OXPHOS enhancement in MM cells. MATERIALS AND METHODS: The expression of OXPHOS genes and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was analyzed using bioinformatics analyses, followed by verification in MM cell lines. The effects of SR18292 on OXPHOS were measured by qRT-PCR, Western blot, transmission electron microscopy, oxygen consumption rate and so on. The proliferation and apoptosis were evaluated by CCK-8, flow cytometry and Western blot. The efficiency and safety of SR18292 were assessed in a mouse model of MM. KEY FINDINGS: The OXPHOS genes were generally overexpressed in MM cells, which was associated with poorer prognosis of MM patients. PGC-1α, a transcriptional coactivator, was upregulated in MM cells, and MM patients with higher PGC-1α expression exhibited increased enrichment of the OXPHOS gene set. Treatment with SR18292 (an inhibitor of PGC-1α) significantly impaired the proliferation and survival of MM cells due to OXPHOS metabolism dysfunction, which leads to energy exhaustion and oxidative damage. Besides, SR18292 potently inhibited tumor growth at a well-tolerated dose in MM model mice. SIGNIFICANCE: The overexpression of OXPHOS gene set mediated by upregulated PGC-1α provides a structural basis for enhanced OXPHOS in MM cells, and SR18292 (a PGC-1α inhibitor) exerts potent antimyeloma effects, offering a potential tangible avenue for MM therapy.


Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Fosforilação Oxidativa , Propanóis/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mieloma Múltiplo/ultraestrutura , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Prognóstico , Propanóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 11(1): 2996, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32533060

RESUMO

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hematopoese/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas/genética , Transplante Autólogo , Proteína Supressora de Tumor p53/genética , Adulto Jovem
15.
Nat Commun ; 11(1): 2666, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471990

RESUMO

Multiple myeloma is a plasma cell blood cancer with frequent chromosomal translocations leading to gene fusions. To determine the clinical relevance of fusion events, we detect gene fusions from a cohort of 742 patients from the Multiple Myeloma Research Foundation CoMMpass Study. Patients with multiple clinic visits enable us to track tumor and fusion evolution, and cases with matching peripheral blood and bone marrow samples allow us to evaluate the concordance of fusion calls in patients with high tumor burden. We examine the joint upregulation of WHSC1 and FGFR3 in samples with t(4;14)-related fusions, and we illustrate a method for detecting fusions from single cell RNA-seq. We report fusions at MYC and a neighboring gene, PVT1, which are related to MYC translocations and associated with divergent progression-free survival patterns. Finally, we find that 4% of patients may be eligible for targeted fusion therapies, including three with an NTRK1 fusion.


Assuntos
Fusão Gênica/genética , Histona-Lisina N-Metiltransferase/genética , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA/genética , Perfilação da Expressão Gênica/métodos , Histona-Lisina N-Metiltransferase/biossíntese , Humanos , Imunoglobulinas/genética , Pessoa de Meia-Idade , Intervalo Livre de Progressão , RNA Longo não Codificante/genética , RNA-Seq/métodos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor trkA/genética , Proteínas Repressoras/biossíntese
16.
Nat Commun ; 11(1): 1917, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317634

RESUMO

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/genética , Desaminase APOBEC-1/metabolismo , Citidina Desaminase/metabolismo , Análise Mutacional de DNA , Detecção Precoce de Câncer , Exoma , Genética , Centro Germinativo/patologia , Humanos , Modelos Lineares , Antígenos de Histocompatibilidade Menor/metabolismo , Mutação , Proteínas/metabolismo , Edição de RNA , RNA Mensageiro , Análise de Célula Única
17.
BMC Bioinformatics ; 21(1): 144, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293247

RESUMO

BACKGROUND: The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data. RESULTS: TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications. CONCLUSIONS: We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Software , Algoritmos , Neoplasias da Mama/genética , Feminino , Dosagem de Genes , Genoma Humano , Genômica , Humanos , Linfoma Folicular/genética , Mieloma Múltiplo/genética , Mutação , Medicina de Precisão , Navegador
19.
Nat Commun ; 11(1): 1931, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321912

RESUMO

Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/administração & dosagem , Spliceossomos/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Feminino , Humanos , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Oligopeptídeos/administração & dosagem , Processamento de RNA/efeitos dos fármacos , Spliceossomos/genética , Spliceossomos/metabolismo , Spliceossomos/microbiologia
20.
Hematology ; 25(1): 176-180, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32345147

RESUMO

Objectives: Multiple myeloma (MM) often develops as a secondary primary malignancy (SPM). The retinoblastoma susceptibility gene (RB1) was the first tumour suppressor gene to be identified. We pooled and analyzed available data to compare the incidence of RB1 gene deletions and other cytogenetic abnormalities in patients with MM alone or as an SPM.Methods: We conducted a retrospective study of 475 patients. The experimental group comprised 18 patients with MM as an SPM, and the control group comprised 457 MM patients. We analyzed the baseline information in both groups, and used the odds ratio (OR), 95% confidence interval (CI), and forest plot to determine the incidence of SPMs with and without cytogenetic abnormalities.Results: The incidence of RB1 gene deletion was higher in the experimental group. There was no significant difference in other cytogenetic abnormalities.Conclusions: RB1 gene deletions appear to be associated with MM that develops as an SPM.


Assuntos
Aberrações Cromossômicas , Mieloma Múltiplo/genética , Segunda Neoplasia Primária/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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