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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(6): 2097-2012, 2020 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-33283749

RESUMO

Enhancer of zeste homolog 2(EZH2) is a histone methyltransferase which regulate gene expression through epigenetic machinery. The abnormal expression of EZH2 has been described in many cancer types. With in-depth study, it was found that EZH2 is involved in the occurrence and development in many kinds of malignant hematologic disease which may play a dual role of oncogenes and tumor suppressor genes. In recent years, the emergence of EZH2 inhibitors provide a new option for the future treatment of hematological malignancies. In this review, the expression and clinical significance of EZH2 in various of hematological tumors were summarized briefly.


Assuntos
Neoplasias Hematológicas , Neoplasias , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias Hematológicas/genética , Humanos , Oncogenes , Pesquisa
2.
Zhonghua Yi Xue Za Zhi ; 100(43): 3443-3447, 2020 Nov 24.
Artigo em Chinês | MEDLINE | ID: mdl-33238676

RESUMO

Objective: To explore the application and discovery of genotyping, gene sequencing, and gene expression analysis in the determination of ABO blood group subtypes and antigen expression abnormalities in hematological malignancies patients. Methods: From June 2019 to May 2020, three clinical cases were found with forward and reverse ABO typing discrepancy or atypical serologic agglutination pattern in the laboratory and blood transfusion department of Hebei Yanda Ludaopei Hospital were selected. Sequence-specific primer PCR (PCR-SSP) and Sanger sequencing of ABO gene coding regions were performed to determine the ABO genotypes, and whole transcriptome sequencing was used to analyze ABO and FUT1 gene expression levels. Results: A 12-year-old female acute lymphoblastic leukemia patient was determined as O.01.02 and BA.04 sub-genotype, corresponding to the serological B(A) subtype, and her ABO gene expression was normal (354.80). A 41-year-old female acute myeloid leukemia patient was determined as A1.02 and B.01 genotype, corresponding to the serological A(1)B phenotype, and her ABO gene expression was significantly reduced (45.70). A 42-year-old male with myelodysplastic syndrome and myelofibrosis was determined as A1.02 and A2.05 sub-genotype, corresponding to the serological A(1) and A(2) phenotype, respectively, and his ABO expression was negative. FUT1 expression was in the normal range in all three cases. The clinical blood product infusion strategy was formulated according to the genotype and the corresponding immunological subtype, and no significant transfusion-related adverse reactions occurred. Conclusion: Blood group sub-genotypes or aberrant gene expression can lead to ambiguities in serological blood group determination in hematological malignancies patients. ABO genotyping and gene expression analysis can help in this scenario and escort blood product infusion safety.


Assuntos
Tipagem e Reações Cruzadas Sanguíneas , Neoplasias Hematológicas , Sistema ABO de Grupos Sanguíneos/genética , Adulto , Alelos , Criança , Genótipo , Neoplasias Hematológicas/genética , Humanos , Masculino , Fenótipo
3.
Nat Commun ; 11(1): 5660, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168830

RESUMO

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8+ T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses; such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies.


Assuntos
Retrovirus Endógenos/genética , Neoplasias Hematológicas/virologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Linfócitos T CD8-Positivos , Epigênese Genética , Epitopos de Linfócito T , Perfilação da Expressão Gênica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia , Monitorização Imunológica , Células Mieloides , Neoplasias
4.
Nat Commun ; 11(1): 5834, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203900

RESUMO

Recent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). The genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyze a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observe a specific mutational pattern and an average of 25-fold increase of mutation rates in XP-C versus sporadic leukemia which we presume leads to its elevated incidence and early appearance. We describe a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients.


Assuntos
Neoplasias Hematológicas/genética , Taxa de Mutação , Xeroderma Pigmentoso/genética , Criança , Pré-Escolar , Reparo do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Humanos , Lactente , Leucemia/genética , Sequenciamento Completo do Genoma , Xeroderma Pigmentoso/patologia
5.
Sci Rep ; 10(1): 16532, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020578

RESUMO

Fungal infections represent a worrisome complication in hematologic cancer patients and in the absence of disease specific symptoms, it is important to establish new biological indicators, which can be used during mould-active prophylaxis. Recently, miRNAs have appeared as candidate diagnostic and prognostic markers of several diseases. A pilot clinical study was performed to evaluate the diagnostic utility of 14 microRNAs which can be related to invasive fungal infections. Based on our data miR-142-3p, miR-142-5p, miR-26b-5p and miR-21-5p showed significant overexpression (p < 0.005) due to invasive aspergillosis in hemato-oncology patients with profound neutropenia. A tetramiR assay was designed to monitor peripheral blood specimens. Optimal cut-off was estimated by using the median value (fold change 1.1) of the log10 transformed gene expressions. The biomarker panel was evaluated on two independent sample cohorts implementing different antimicrobial prophylactic strategies. The receiver operating characteristic analysis with area under the curve proved to be 0.97. Three miRNAs (miR-142-5p, miR-142-3p, miR-16-5p) showed significant expression alterations in episodes with sepsis. In summary, the tetramiR assay proved to be a promising diagnostic adjunct with sufficient accuracy and sensitivity to trace invasive aspergillosis in hemato-oncology patients.


Assuntos
Aspergilose/diagnóstico , Aspergilose/genética , Ácidos Nucleicos Livres/genética , MicroRNA Circulante/genética , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/metabolismo , MicroRNA Circulante/sangue , MicroRNA Circulante/metabolismo , Feminino , Perfilação da Expressão Gênica , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/genética , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/genética , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neutropenia/complicações , Neutropenia/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sepse/sangue , Sepse/genética
6.
Exp Hematol ; 92: 75-88.e10, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33017633

RESUMO

Human leukocyte antigen class I (HLA-I) genotype has been found to influence cancer development through the presentation of mutational neoepitopes. However, our understanding of its effect on the development of myeloproliferative neoplasms (MPNs) remains limited. We aimed to elucidate the putative protective role of HLA-I alleles in the development of JAK2 V617F-driven MPNs using a population genetics approach. The variability of the HLA-I genotype had no effect on the presence of JAK2 V617F mutation. However, three alleles were found to be inversely correlated with the presence of JAK2 V617F mutation: HLA-A*02:01 (p = 0.036), HLA-B*35:01 (p = 0.017), and HLA-C*15:02 (p = 0.033). The HLA-B*35:01 allele was predicted to bind to a 9-mer peptide derived from JAK2 V617F mutant protein. Gene expression analysis revealed a lower expression of HLA-A and -B in MPN CD34+ cells compared with normal CD34+ cells, which was modulated by ruxolitinib and interferon-α treatment. In summary, we provide robust evidence that specific HLA-I molecules restrict JAK2 V617F-driven oncogenesis. JAK2 V617F+ stem cells evade immune surveillance through downregulation of the HLA-I expression. Therefore, the presence of specific HLA-I alleles might be a predictive marker for response to certain immunotherapies upregulating HLA-I expression. Finally, our findings have implications in the development of mutational neoepitope-based vaccines in MPNs.


Assuntos
Alelos , Carcinogênese , Neoplasias Hematológicas , Antígenos de Histocompatibilidade Classe I , Janus Quinase 2 , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos , Substituição de Aminoácidos , Carcinogênese/genética , Carcinogênese/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia
7.
Anticancer Res ; 40(10): 5707-5713, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988896

RESUMO

BACKGROUND/AIM: Genetic variations of the non-coding RNA gene, ANRIL, have been associated with human diseases including cancer, type-2 diabetes, and atherosclerosis. In the present study, we investigated the potential associations of select ANRIL single nucleotide polymorphisms (SNPs) with overall survival and other clinical outcomes in adult patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: Genomic DNA was extracted from whole blood samples from 103 adult patients with hematologic malignancies who had received allo-HSCT followed by oral tacrolimus therapy. The genotypes of four select ANRIL SNPs, rs564398, rs1063192, rs2151280, and rs2157719 were determined using qRT-PCR-based genotyping assays. RESULTS: rs2151280 (C->T) in ANRIL was associated with worse overall survival in these patients (CT/CC vs. TT). Contrarily, rs2151280 and the other select ANRIL SNPs were not associated with death at Day-100 after transplantation, the incidence of graft-versus-host disease (GVHD), acute kidney injury (AKI), and neurotoxicity in the study cohort. CONCLUSION: rs2151280 represents a potential prognostic biomarker for overall survival in adult patients with hematologic malignancies after allo-HSCT.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , RNA Longo não Codificante/genética , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Idoso , Feminino , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Tacrolimo/farmacocinética , Transplante Homólogo/efeitos adversos
8.
Sci Rep ; 10(1): 13584, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788680

RESUMO

Warburg effect or aerobic glycolysis provides selective growth advantage to aggressive cancers. However, targeting oncogenic regulators of Warburg effect has always been challenging owing to the wide spectrum of roles of these molecules in multitude of cells. In this study, we present ADP-dependent glucokinase (ADPGK) as a novel glucose sensor and a potential onco-target in specifically high-proliferating cells in Burkitt's lymphoma (BL). Previously, we had shown ADPGK to play a major role in T-cell activation and induction of Warburg effect. We now report ADPGK knock-out Ramos BL cells display abated in vitro and in vivo tumour aggressiveness, via tumour-macrophage co-culture, migration and Zebrafish xenograft studies. We observed perturbed glycolysis and visibly reduced markers of Warburg effect in ADPGK knock-out cells, finally leading to apoptosis. We found repression of MYC proto-oncogene, and up to four-fold reduction in accumulated mutations in translocated MYC in knock-out cells, signifying a successful targeting of the malignancy. Further, the activation induced differentiation capability of knock-out cells was impaired, owing to the inability to cope up with increased energy demands. The effects amplified greatly upon stimulation-based proliferation, thus providing a novel Burkitt's lymphoma targeting mechanism originating from metabolic catastrophe induced in the cells by removal of ADPGK.


Assuntos
Proliferação de Células/genética , Glucoquinase/genética , Neoplasias Hematológicas/genética , Peixe-Zebra/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Cocultura , Técnicas de Inativação de Genes , Glucoquinase/metabolismo , Glicólise/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Células Jurkat , Macrófagos/metabolismo , Macrófagos/patologia , Linfócitos T/metabolismo , Células THP-1 , Transplante Heterólogo , Peixe-Zebra/metabolismo
9.
Cancer Res ; 80(18): 3799-3802, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32732221

RESUMO

Myc and Ras are two of the most commonly activated oncogenes in tumorigenesis. Together and independently they regulate many cancer hallmarks including proliferation, apoptosis, and self-renewal. Recently, they were shown to cooperate to regulate host tumor microenvironment programs including host immune responses. But, is their partnership always cooperative or do they have distinguishable functions? Here, we provide one perspective that Myc and Ras cooperation depends on the genetic evolution of a particular cancer. This in turn, dictates when they cooperate via overlapping and identifiably distinct cellular- and host immune-dependent mechanisms that are cancer type specific.


Assuntos
Neoplasias da Mama/genética , Genes myc/fisiologia , Genes ras/fisiologia , Neoplasias Hematológicas/genética , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética , Adenocarcinoma/genética , Carcinogênese/genética , Carcinogênese/imunologia , Fenômenos Fisiológicos Celulares/genética , Feminino , Humanos , Ativação Transcricional
11.
PLoS One ; 15(8): e0236338, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785215

RESUMO

Dysregulation of BCL2 is a pathophysiology observed in haematological malignancies. For implementation of available treatment-options it is preferred to know the relative quantification of BCL2 mRNA with appropriate reference genes. For the choice of reference genes-(i) Reference Genes were selected by assessing variation of >60,000 genes from 4 RNA-seq datasets of haematological malignancies followed by filtering based on their GO biological process annotations and proximity of their chromosomal locations to known disease translocations. Selected genes were experimentally validated across various haematological malignancy samples followed by stability comparison using geNorm, NormFinder, BestKeeper and RefFinder. (ii) 43 commonly used Reference Genes were obtained from literature through extensive systematic review. Levels of BCL2 mRNA was assessed by qPCR normalized either by novel reference genes from this study or GAPDH, the most cited reference gene in literature and compared. The analysis showed PTCD2, PPP1R3B and FBXW9 to be the most unregulated genes across lymph-nodes, bone marrow and PBMC samples unlike the Reference Genes used in literature. BCL2 mRNA level shows a consistent higher expression in haematological malignancy patients when normalized by these novel Reference Genes as opposed to GAPDH, the most cited Reference Gene. These reference genes should also be applicable in qPCR platforms using Taqman probes and other model systems including cell lines and rodent models. Absence of sample from healthy-normal individual in diagnostic cases call for careful selection of Reference Genes for relative quantification of a biomarker by qPCR.BCL2 can be used as molecular diagnostics only if normalized with a set of reference genes with stable yet low levels of expression across different types of haematological malignancies.


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Neoplasias Hematológicas/diagnóstico , Proteínas Proto-Oncogênicas c-bcl-2/isolamento & purificação , RNA Mensageiro/isolamento & purificação , RNA-Seq/normas , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Medula Óssea/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Estudos de Viabilidade , Regulação Neoplásica da Expressão Gênica , Genes Essenciais , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Leucócitos Mononucleares , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/sangue , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/normas , Padrões de Referência
12.
Am J Hematol ; 95(11): 1361-1367, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32777106

RESUMO

Chromosomal abnormalities are frequently observed in patients with chronic lymphocytic leukemia (CLL) and have prognostic value. Deletions of the short arm of chromosome 17 (and/or mutations TP53) predict resistance to chemoimmunotherapy and shorter progression-free survival after targeted therapies. Although the complex karyotype (CK) is strongly predictive of a poor prognosis in hematologic malignancies such acute myeloid leukemia or myelodysplastic syndrome, its value in CLL is subject to debate. Here, we review the literature on the CK in CLL and examine its prognostic value with different treatments. We also propose a standardized method for defining a CK in all types of hematopoietic neoplasm.


Assuntos
Cariótipo Anormal , Cromossomos Humanos Par 17/genética , Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Proteína Supressora de Tumor p53/genética , Intervalo Livre de Doença , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Taxa de Sobrevida
14.
Curr Opin Oncol ; 32(5): 535-544, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32657797

RESUMO

PURPOSE OF REVIEW: MiRNAs are critical regulators for gene expression. Numerous studies have revealed how miRNAs contribute to the pathogenesis of hematologic malignancies. RECENT FINDINGS: The identification of novel miRNA regulatory factors and pathways crucial for miRNA dysregulation has been linked to hematologic malignancies. miRNA expression profiling has shown their potential to predict outcomes and treatment responses. Recently, targeting miRNA biogenesis or pathways has become a promising therapeutic strategy with recent miRNA-therapeutics being developed. SUMMARY: We provide a comprehensive overview of the role of miRNAs for diagnosis, prognosis, and therapeutic potential in hematologic malignancies.


Assuntos
Neoplasias Hematológicas/genética , MicroRNAs/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , MicroRNAs/biossíntese , Terapia de Alvo Molecular , Prognóstico
15.
Cancer Sci ; 111(9): 3367-3378, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619037

RESUMO

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).


Assuntos
Biomarcadores Tumorais , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
16.
Am J Hematol ; 95(11): 1314-1323, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32720700

RESUMO

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.


Assuntos
Corticosteroides/administração & dosagem , Eosinofilia , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Fusão Oncogênica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Fatores de Poliadenilação e Clivagem de mRNA , Adulto , Intervalo Livre de Doença , Eosinofilia/sangue , Eosinofilia/tratamento farmacológico , Eosinofilia/genética , Eosinofilia/mortalidade , Feminino , França/epidemiologia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/mortalidade , Proteínas de Fusão Oncogênica/sangue , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/sangue , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Estudos Retrospectivos , Taxa de Sobrevida , Triptases/sangue , Vitamina B 12/sangue , Fatores de Poliadenilação e Clivagem de mRNA/sangue , Fatores de Poliadenilação e Clivagem de mRNA/genética
17.
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
18.
Nat Commun ; 11(1): 3390, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636395

RESUMO

Immunoglobulin (Ig) gene rearrangements and oncogenic translocations are routinely assessed during the characterization of B cell neoplasms and stratification of patients with distinct clinical and biological features, with the assessment done using Sanger sequencing, targeted next-generation sequencing, or fluorescence in situ hybridization (FISH). Currently, a complete Ig characterization cannot be extracted from whole-genome sequencing (WGS) data due to the inherent complexity of the Ig loci. Here, we introduce IgCaller, an algorithm designed to fully characterize Ig gene rearrangements and oncogenic translocations from short-read WGS data. Using a cohort of 404 patients comprising different subtypes of B cell neoplasms, we demonstrate that IgCaller identifies both heavy and light chain rearrangements to provide additional information on their functionality, somatic mutational status, class switch recombination, and oncogenic Ig translocations. Our data thus support IgCaller to be a reliable alternative to Sanger sequencing and FISH for studying the genetic properties of the Ig loci.


Assuntos
Genes de Imunoglobulinas , Hibridização in Situ Fluorescente/métodos , Oncogenes , Translocação Genética , Algoritmos , Estudos de Coortes , Genoma Humano , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Switching de Imunoglobulina , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Software , Sequenciamento Completo do Genoma
19.
Mayo Clin Proc ; 95(7): 1482-1498, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571604

RESUMO

With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromes-such as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopenias-also have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.


Assuntos
Neoplasias Hematológicas/genética , Síndromes Neoplásicas Hereditárias/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Medicina de Precisão/métodos
20.
Nature ; 584(7819): 136-141, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581363

RESUMO

Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1-9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank10. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3 and TM2D3). Three of the genes (MRE11, NBN and ATM) encode components of the MRN-ATM pathway, which limits cell division after DNA damage and telomere attrition11-13; another two (MPL and SH2B3) encode proteins that regulate the self-renewal of stem cells14-16. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.


Assuntos
Evolução Clonal/genética , Células Clonais/metabolismo , Hematopoese/genética , Herança Multifatorial/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Divisão Celular/genética , Aberrações Cromossômicas , Células Clonais/citologia , Células Clonais/patologia , Feminino , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Mosaicismo , Reino Unido
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