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1.
J Clin Pathol ; 72(11): 778-782, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473630

RESUMO

SF3B1 is the largest subunit of the Spliceosome Factor 3b (SF3B) complex and part of the U2 small nuclear ribosomal protein. It functions as an important part of spliceosomal assembly, converting precursor messenger RNA (mRNA) to mRNA ready for ribosomal translation. Mutations of SF3B1 are commonly seen in myelodysplastic syndromes with ring sideroblasts (MDS-RS)and MDS/myeloproliferative neoplasm (MPN-RS-T). These mutations are typically heterozygous missense substitutions, of which, 55% involve K700E. MDS-RS and MDS/MPN-RS-T usually carry a more favourable prognosis than other subtypes of MDS. SF3B1 itself does not influence survival in these conditions, but does correlate with increased thrombotic risk. Mutated SF3B1 is present in 9%-15% of chronic lymphocytic leukaemia cases and on its own correlates with improved responsiveness to ibrutinib, but is associated with additional adverse genetic abnormalities including TP53 and ATM mutations, which traditionally confer adverse outcomes.


Assuntos
Biomarcadores Tumorais/genética , Eritroblastos/patologia , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Síndromes Mielodisplásicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Fenótipo , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Prognóstico , Conformação Proteica , Fatores de Processamento de RNA/química , Fatores de Processamento de RNA/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo , Relação Estrutura-Atividade
2.
Nat Commun ; 10(1): 3615, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399598

RESUMO

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.


Assuntos
Epigênese Genética/genética , Epigênese Genética/fisiologia , Epigenômica , Predisposição Genética para Doença/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos B/metabolismo , Sequência de Bases , Cromatina/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição
3.
Med Oncol ; 36(9): 79, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375939

RESUMO

Chronic lymphocytic leukemia (CLL) is one of the most frequent lymphoproliferative diseases. CLL is characterized by unusual heterogeneity, which probably reflects its biological and genetic lack of homogeneity. Clonal chromosome aberrations belong to the most important prognostic and predictive factors in CLL. This research was aimed at observing clonal evolution in CLL at the chromosomal level, and assessing its clinical significance in relation to selected prognostic factors. The study involved 72 untreated patients with CLL. The preliminary investigations using cytogenetic banding analysis (CBA) and FISH were performed at the time of diagnosis, and again after about 24 months to observe clonal changes (clonal evolution). In addition, other parameters were evaluated, i.e., the expression of ZAP-70 kinase, CD38 antigen, and the mutation statuses of IGVH and NOTCH1 genes. Classic prognostic factors, i.e., categorized ZAP70 and CD38 expressions as well as mutations in IGVH and NOTCH1 genes did not influence the course of clonal evolution in the examined group of patients. Clonal evolution was detected in 45.8% of patients by means of CBA, and in 19.4% patients with FISH. Analysis of chromosomal aberrations in the examined group of patients showed that the incidence of 17p deletions and translocations in karyotypes has a negative impact on overall survival. CE was found to be a risk factor for the occurrence of disease progression (OR = 2.22). Our observations indicate that combined CBA and FISH are the most optimal techniques for monitoring clonal evolution in the course of CLL.


Assuntos
Evolução Clonal/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Bandeamento Cromossômico , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida
5.
Blood ; 134(8): 688-698, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31292113

RESUMO

Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.


Assuntos
Metilação de DNA , Leucemia Linfocítica Crônica de Células B/genética , Biomarcadores Tumorais/genética , Progressão da Doença , Epigênese Genética , Loci Gênicos , Testes Genéticos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Prognóstico
6.
Nat Commun ; 10(1): 2969, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278357

RESUMO

Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.


Assuntos
Análise Mutacional de DNA/normas , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Mieloide Aguda/genética , Mieloma Múltiplo/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Biologia Computacional/normas , Análise Mutacional de DNA/métodos , Conjuntos de Dados como Assunto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Mutação , Guias de Prática Clínica como Assunto , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/normas
7.
Nat Rev Clin Oncol ; 16(11): 684-701, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31278397

RESUMO

Chronic lymphocytic leukaemia (CLL), the most frequent type of leukaemia in adults, is a lymphoproliferative disorder that is characterized by the expansion of monoclonal, mature CD5+CD23+ B cells in the peripheral blood, secondary lymphoid tissues and bone marrow. CLL is an incurable disease with a heterogeneous clinical course, for which the treatment decision still relies on conventional parameters (such as clinical stage and lymphocyte doubling time). During the past 5 years, relevant advances have been made in understanding CLL biology. Indeed, substantial progress has been made in the identification of the putative cell of origin of CLL, and comprehensive studies have dissected the genomic, epigenomic and transcriptomic landscape of CLL. Advances in clinical management include improvements in our understanding of the prognostic value of different genetic lesions, particularly those associated with chemoresistance and progression to highly aggressive forms of CLL, and the advent of new therapies targeting crucial biological pathways. In this Review, we discuss new insights into the genetic lesions involved in the pathogenesis of CLL and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , Humanos
8.
Blood ; 134(5): 432-444, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151986

RESUMO

Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-29b to ROR1+ CLL cells leading to downregulation of DNMT1 and DNMT3A, modulation of global DNA methylation, decreased SP1, and increased p21 expression in cell lines and primary CLL cells in vitro. Furthermore, using an Eµ-TCL1 mouse model expressing human ROR1, we report the therapeutic benefit of enhanced survival via cellular reprograming by downregulation of DNMT1 and DNMT3A in vivo. Gene expression profiling of engrafted murine leukemia identified reprogramming of cell cycle regulators with decreased SP1 and increased p21 expression after targeted miR-29b treatment. This finding was confirmed by protein modulation, leading to cell cycle arrest and survival benefit in vivo. Importantly, SP1 knockdown results in p21-dependent compensation of the miR-29b effect on cell cycle arrest. These studies form a basis for leukemic cell-targeted delivery of miR-29b as a promising therapeutic approach for CLL and other ROR1+ B-cell malignancies.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , MicroRNAs/administração & dosagem , MicroRNAs/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Taxa de Sobrevida , Nanomedicina Teranóstica , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Blood ; 134(7): 641-644, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243043

RESUMO

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Fosfolipase C gama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação
10.
Anticancer Res ; 39(6): 2805-2810, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177117

RESUMO

BACKGROUND/AIM: Galectins belong to the family of galactose-binding proteins known to play an important role in the processes of cell proliferation, differentiation, migration and neoplastic progression. Herein, we studied the expression of galectin-3 (Gal-3) in chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: The expression of Gal-3 was analyzed by means of multiparametric flow cytometry in normal and pathological B-cells from peripheral blood and bone marrow samples of 67 patients with CLL. RESULTS: Pathological B-cells expressed significantly higher levels of cytoplasmic Gal-3 than normal B-cells. Moreover, overexpression of cytoplasmic Gal-3 was observed in the prognostically poorest subgroup of CLL patients, namely those with 17p deletion. CONCLUSION: Our results indicate a possible role of galectin-3 in CLL pathophysiology and its potential value as a prognostic marker and therapeutic target.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Galectina 3/genética , Leucemia Linfocítica Crônica de Células B/genética , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Citoplasma/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Anticancer Res ; 39(6): 2861-2869, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177124

RESUMO

BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis. MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization. RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls. CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.


Assuntos
Arildialquilfosfatase/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Aberrações Cromossômicas , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade
12.
Zhonghua Xue Ye Xue Za Zhi ; 40(5): 378-383, 2019 May 14.
Artigo em Chinês | MEDLINE | ID: mdl-31207701

RESUMO

Objective: To analyze the survival and first-line immune-chemotherapy (CIT) of chronic lymphocytic leukemia (CLL) with abnormal TP53 gene in the era of traditional CIT. Methods: The clinical data of 118 CLL patients diagnosed from January 2003 to August 2017 were collected. Survival was analyzed according to indicators including sex, age, Binet risk stratification, B symptoms, ß(2)-microglobulin (ß(2)-MG) , immunoglobulin heavy chain variable region gene (IGHV) mutation status, chromosome karyotype and TP53 gene deletion/mutation. The efficacy of first-line CIT of 101 CLL patients was further analyzed. Results: Among 118 patients, median progression-free survival (PFS) was 12 (95%CI 10.148-13.852) months and median overall survival (OS) was 53 (95%CI 41.822-64.178) months, only 30.5% patients survived over 5 years. Low ß(2)-MG<3.5 mg/L indicated longer PFS (P=0.027) , female and Binet A patients had longer OS (P=0.011 and 0.013, respectively) . Of 118 patients, 17 (14.4%) didn't receive any therapy until follow-up time or the dead time. Among the 101 patients who received ≥1 CIT, median time to first treatment (TTFT) was 1 (0-62) months, patients in Binet A had longer TTFT (P<0.001) compared to the patients in Binet B/C. According to statistical needs, we divided those first-line CIT into four groups: there were 30 cases (29.7%) in mild chemotherapy group (mainly treated with nitrogen mustard phenylbutyrate or rituximab alone) , 32 cases (31.7%) in the fludarabine-containing group, 23 cases (22.8%) in high-dose methyprednisolone (HDMP) containing group and 16 cases (15.8%) in the other chemotherapy group. The first regimen contained HDMP can bring longer PFS (P<0.001) , however the OS between four groups had no statistical differences. Conclusion: CLL patients with abnormal TP53 gene had poor response to immunotherapy, rapid clinical progressing, first-line immunotherapy containing HDMP can prolong PFS and will create an opportunity for patients to participate in clinical trials of novel drugs.


Assuntos
Leucemia Linfocítica Crônica de Células B , Proteína Supressora de Tumor p53/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Genes p53 , Humanos , Imunoterapia , Leucemia Linfocítica Crônica de Células B/genética , Análise de Sobrevida
13.
Life Sci ; 232: 116583, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226417

RESUMO

TP53 mutation is an indicator of poor prognostic in chronic lymphocytic leukemia (CLL). Worse still, CLL patients with TP53 mutation are associated with poor efficacy to current chemotherapeutic, such as Fludarabine. Here, we confirmed that high expression of HDAC1 in CLL patients with TP53 mutation, which is closely related to poor prognosis and drug-resistance. Subsequently, we demonstrated Entinostat (HDAC1 inhibitor) combination with Fludarabine significantly induced apoptosis in TP53 mutations CLL cells. Its mechanism was associated with up-regulation of the pro-apoptotic protein Bax and the down-regulation of HDAC1, HO-1 and BCL-2 proteins. More importantly, we also confirmed that upregulation of HDAC1 could resistant Entinostat-induced apoptosis in TP53 mutations CLL cells by activating the HDAC1/P38/HO-1 pathway. In vivo, we found that Entinostat combination with Fludarabine significantly induced tumor cells apoptosis and prolong survival time in xenograft mouse model. Finally, combining vitro and vivo experiments, we presented the first demonstration that Entinostat combination with Fludarabine had a synergistic effect on the induction of apoptosis in TP53 mutations CLL cells. In conclusion, we provide valuable pre-clinical experimental evidence for the treatment of CLL patients with poor prognosis, especially for TP53 mutations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/farmacologia , Heme Oxigenase-1/metabolismo , Histona Desacetilase 1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piridinas/farmacologia , Proteína Supressora de Tumor p53/genética , Vidarabina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Benzamidas/administração & dosagem , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Histona Desacetilase 1/biossíntese , Histona Desacetilase 1/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/administração & dosagem , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Vidarabina/administração & dosagem , Vidarabina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
N Engl J Med ; 380(22): 2095-2103, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31141631

RESUMO

BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Leucemia Linfocítica Crônica de Células B/genética , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Neutropenia/induzido quimicamente , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Sulfonamidas/efeitos adversos
15.
Future Oncol ; 15(19): 2227-2239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31137964

RESUMO

P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across different prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Immune-related effects are the main reason for treatment suspension, thus affecting survival benefit. Nevertheless, the correct management of adverse events, eventually including dose modification, allows patients to remain on treatment. In conclusion, duvelisib represents a promising treatment in chronic lymphocytic leukemia and a salvage therapy after ibrutinib.


Assuntos
Isoquinolinas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Avaliação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Isoquinolinas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Terapia de Salvação/efeitos adversos
16.
Klin Onkol ; 32(Supplementum1): 167-170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31064191

RESUMO

BACKGROUND: Chronic lymphocytic leukemia (CLL) is clinically and biologically highly variable disease which is closely related with multiple cellular and molecular markers, including sequence motifs of B-cell receptors. These motifs are highly similar (stereotyped) within one third of CLL patients and create homogeneous groups called stereotyped CLL subsets. The homogeneity is reflected also in clinical and biological characteristics of the disease. To facilitate access to the information about individual subsets, we have created a publicly available web-based tool Encyclopedia of CLL Subsets. MATERIALS AND METHODS: The Encyclopedia of CLL subsets belongs to our bioinformatics platform Antigen Receptor Research Tool (ARResT) developed for analysis, clustering, and annotation of immunoglobulin sequences. To gather primary knowledge about the subsets, we have analyzed a dataset of 7,500 CLL patients published by Agathangelidis et al in 2012 [1]. We have created an overview of major stereotyped subsets and their characteristics. Additional clinical and cytogenomic information about individual subsets has been obtained by machine text processing of available literature from server PubMed and is regularly updated. RESULTS: We have created a unique web-based application Encyclopedia of CLL Subsets available from http: //arrest.tools/subsets for an interactive access to the information about stereotyped CLL subsets. A user can obtain and compare basic information about the major subsets including their clinical and cytogenomic characteristics. These have been manually curated from machine processed results from PubMed database by experts in CLL research. Through the Encyclopedias user interface, user can also directly use our published tool ARResT/AssignSubsets to assign new immunoglobulin sequences to the major subsets. CONCLUSION: The Encyclopedia of CLL Subsets is a publicly available online tool facilitating access to the most recent research knowledge about stereotyped CLL subsets and enabling analysis of own data and interpretation of the results. This gives the Encyclopedia a great potential for its use in clinical routine. This work was supported by Czech Ministry of Health grant No. 34272A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 4. 3. 2019.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Bases de Dados Factuais , Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/patologia , Receptores de Antígenos de Linfócitos B/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética
17.
Int J Lab Hematol ; 41(4): 561-571, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31112375

RESUMO

INTRODUCTION: Conventional cytogenetics (CC) is important in diagnosis, therapy, monitoring of post-transplant bone marrow, and prognosis assessment of acute lymphoblastic leukemia (ALL). However, due to the nature of ALL, CC often encounters difficulties of complex karyotype, poor chromosome morphology, low mitotic index, or normal cells dividing only. In contrast, chromosomal microarray analysis (CMA) showed a specificity >99% and a sensitivity of 100% in chronic lymphocytic leukemia (CLL) patients. Here, we report our experience with CMA on adult ALL patients. METHODS: Thirty-three bone marrow/blood samples from ALL patients (aged 18-79 years, median 44) at diagnosis/relapse, analyzed by CC and/or fluorescence in situ hybridization (FISH), were recruited. Chromosomal microarray analysis results were compared with CC. Fluorescence in situ hybridization analysis, if available, was applied when there was a discrepancy. RESULTS: Copy-neutral loss-of-heterozygosity (CN-LOH) was found in 8 cases (24.2%). Only CN-LOH at 9p was recurrent (3 cases, 9.1%). Copy number alterations (CNAs) were detected in 6 of 9 cases (66.7%) with normal karyotypes, in 3 of 5 cases (60.0%) with sole "balanced" translocations, and in 18 of 19 cases (94.7%) with complex karyotypes. Common CNAs involved CDKN2A/2B (30.3%), IKZF1 (27.3%), PAX5 (9.1%), RB1 (9.1%), BTG1 (6.7%), and ETV6 (6.7%), which regulate cell cycle, B lymphopoiesis, or act as tumor suppressors in ALL. Copy number alteration detection rate by CMA was 81.8% (27 of 33 cases) as compared to 57.6% (19 of 33 cases) by CC. CONCLUSION: Incorporation of CMA as a routine clinical test at the time of diagnosis/relapse, in conjunction with CC and/or FISH, is highly recommended.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Hibridização in Situ Fluorescente , Perda de Heterozigosidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Idoso , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva
18.
BMC Cancer ; 19(1): 515, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142279

RESUMO

BACKGROUND: Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disorder in western countries and is characterized by a remarkable clinical heterogeneity. During the last decade, multiple genomic studies have identified a myriad of somatic events driving CLL proliferation and aggressivity. Nevertheless, and despite the mounting evidence of inherited risk for CLL development, the existence of germline variants associated with clinical outcomes has not been addressed in depth. METHODS: Exome sequencing data from control leukocytes of CLL patients involved in the International Cancer Genome Consortium (ICGC) was used for genotyping. Cox regression was used to detect variants associated with clinical outcomes. Gene and pathways level associations were also calculated. RESULTS: Single nucleotide polymorphisms in PPP4R2 and MAP3K4 were associated with earlier treatment need. A gene-level analysis evidenced a significant association of RIPK3 with both treatment need and survival. Furthermore, germline variability in pathways such as apoptosis, cell-cycle, pentose phosphate, GNα13 and Nitric oxide was associated with overall survival. CONCLUSION: Our results support the existence of inherited conditionants of CLL evolution and points towards genes and pathways that may results useful as biomarkers of disease outcome. More research is needed to validate these findings.


Assuntos
Biomarcadores Tumorais/genética , Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/genética , Sequenciamento Completo do Exoma/métodos , Feminino , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , MAP Quinase Quinase Quinase 4/genética , Masculino , Fosfoproteínas Fosfatases/genética , Análise de Sobrevida
19.
BMC Res Notes ; 12(1): 282, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122288

RESUMO

OBJECTIVE: To investigate the ZAP-70 and CD38 expressions and their combined expressions in Sudanese B-CLL patients and their relationships with clinical and hematological characteristics as well as the disease staging at presentation. RESULTS: In the present cross-sectional descriptive study, analysis of ZAP-70 expression showed that 36/110 (32.7%) patients positively expressed ZAP-70 and insignificant higher presentation in intermediate and at advanced stages as well as no correlation was seen with hematological parameters and clinical features compared with negatively ZAP-70, on the other hand, 41/110 (37.3%) were CD38+ and no significant correlation was shown with the stage at presentation, clinical characteristics (except Splenomegaly, P = 0.02) and hematological parameters. However, in combined expressions of both ZAP-70 and CD38 together, 20/110 (18.2%) were concordantly ZAP-70+/CD38+, 53/110 (48.2%) concordantly ZAP-70-/CD38- and 37/110 (33.6%) either ZAP-70+ or CD38+, and these three groups showed insignificant correlation with clinical (except Splenomegaly, P = 0.03) and hematological parameters, and the stage at presentation. Our data showed the combined analysis of these two markers, lead to classify our patients into three subgroups (either concordant positive, negative or discordant expressions) with statistically insignificant correlation with clinical presentation (except Splenomegaly), hematological parameters and stage at presentation of B-CLL patients.


Assuntos
ADP-Ribosil Ciclase 1/genética , Biomarcadores Tumorais/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Glicoproteínas de Membrana/genética , Esplenomegalia/diagnóstico , Proteína-Tirosina Quinase ZAP-70/genética , ADP-Ribosil Ciclase 1/sangue , ADP-Ribosil Ciclase 1/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Estudos Transversais , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Esplenomegalia/genética , Esplenomegalia/imunologia , Esplenomegalia/patologia , Sudão , Proteína-Tirosina Quinase ZAP-70/sangue , Proteína-Tirosina Quinase ZAP-70/imunologia
20.
Asian Pac J Cancer Prev ; 20(5): 1579-1585, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31128065

RESUMO

Objective: This study aimed at exploring the association of TP53 72Arg/Pro polymorphism and Risk of Chronic Lymphocytic Leukemia and to assess the correlation between TP53 72Arg/Pro polymorphism and clinical parameter, hematological profile and some biological prognostic markers among Sudanese patients with chronic lymphocytic leukemia. Methods: A case-control study was conducted in Khartoum state, Sudan, during the period from April 2017 to April 2018, involved 110 B-CLL patients and 80 healthy volunteers as a control group. Physical examination, Complete Blood Count and Immunophenotype were performed in all patients to confirm the diagnosis. Clinical staging such as Rai and Binet were studied. CD38 and ZAP70 were performed by Flow Cytometry. Blood samples were collected from all participants; DNA was extracted by using ANALYTIKJENA Blood DNA Extraction Kit (Germany) and analyzed TP53 codon 72Arg/Pro Polymorphism by using AS-PCR. The statistical analysis was performed using SPSS version 23.0 software (Chicago, IL, USA). Results: the Arg/Pro was the most frequent genotype in B-CLL patients(50%), followed by Arg/Arg (25.5%) and Pro/Pro (24.5%), whereas in healthy control group Arg/Pro was the most frequent (47.5%), followed by Arg/Arg (45%) and Pro/Pro (7.5%). Our data indicate a higher frequency of homozygous Pro/ Pro in the B-CLL patients as compared to controls with an OR of 4.01 for the Pro/Pro genotype and lower frequency of Arg/Arg genotype in CLL patients as compared to controls with an OR of .42 for the Arg/Arg genotype. Also, the Pro allele showed higher risk than Arg allele (P value=0.000, OR 2.23, 95% CI=1.45-3.41). No significant association between gender, clinical staging systems (Rai, Binet), biological prognostic markers (CD38 expression or ZAP70 expression), and TP53 codon 72Arg/Pro polymorphisms, except Arg/Arg genotype tended to be associated with younger age (P =0.04). Conclusion: Our data suggested that Pro/Pro genotype contribute to increased susceptibility to B-Chronic Lymphocytic Leukemia risk in our population tenfold higher than those had Arg/Arg genotype.


Assuntos
Dipeptídeos/genética , Predisposição Genética para Doença/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Códon , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Sudão , Adulto Jovem
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