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1.
PLoS One ; 15(5): e0233191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453736

RESUMO

The Ikzf1 locus encodes the lymphoid specific transcription factor Ikaros, which plays an essential role in both T and B cell differentiation, while deregulation or mutation of IKZF1/Ikzf1 is involved in leukemia. Tissue-specific and cell identity genes are usually associated with clusters of enhancers, also called super-enhancers, which are believed to ensure proper regulation of gene expression throughout cell development and differentiation. Several potential regulatory regions have been identified in close proximity of Ikzf1, however, the full extent of the regulatory landscape of the Ikzf1 locus is not yet established. In this study, we combined epigenomics and transcription factor binding along with high-throughput enhancer assay and 4C-seq to prioritize an enhancer element located 120 kb upstream of the Ikzf1 gene. We found that deletion of the E120 enhancer resulted in a significant reduction of Ikzf1 mRNA. However, the epigenetic landscape and 3D topology of the locus were only slightly affected, highlighting the complexity of the regulatory landscape regulating the Ikzf1 locus.


Assuntos
Elementos Facilitadores Genéticos/fisiologia , Regulação da Expressão Gênica/fisiologia , Loci Gênicos/fisiologia , Fator de Transcrição Ikaros/biossíntese , Animais , Linhagem Celular , Epigenômica , Genes Reporter , Fator de Transcrição Ikaros/genética , Camundongos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 405-410, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319370

RESUMO

OBJECTIVE: To investigate the prognosis of patients with adult B-cell acute lymphoblastic leukemia (B-ALL) accompanied with Ikaros family zinc finger 1 (IKZF1) mutation, and to explore the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in improving the clinical outcome of patients. METHODS: The clinical data of 164 adult B-ALL patients who received IKZF-1 mutation detection by capillary electrophoresis of bone marrow were collected, and the relationship between the IKZF-1 gene mutation and the prognosis of adult B-ALL patients was analyzed. RESULTS: Among 164 adult B-ALL patients, the patients with IKZF-1 mutation (IKZF-1+) were 80 cases, while the patients without IKZF-1 mutation (IKZF-1-) were 84 cases. Among 80 IKZF-1 positive patients, according to the treatment method after complete remission these patients were divided into HSCT group (48 cases) and chemotherapy group (32 cases). Analysis showed that the 3-year overall survival (OS) and leukemia-free survival (LFS) rates in the IKZF1+ group were much lower. The OS and LFS rate in transplantation group were 50.3%±8.3%, 41.6%±8.5%; the OS and LFS rates in the chemotherapy group were 33.7%±12.8%, 31.5%±9.5%, which were lower than those in the IKZF1- group (the transplantation group: 79.5%±7.6%, 64.0%±8.4%; the chemotherapy group: 54.4%±9.9%, 40.6%±9.6% respectirely (P<0.05). Among 80 B-ALL patients with IKZF-1- mutation, the 3-year OS and LFS rates were significantly higher in the transplantation group (55.3%±7.5%, 48.3%±7.6%) than those in the chemotherapy group (32.9%±11.8%, 28.4%±10.3%) with IKZF1 mutation (P<0.05). CONCLUSION: IKZF1 mutation is an adverse prognostic factor for adult B-ALL patients, However, allo-HSCT significantly improves the OS and LFS of patients and also their clinical outcomes.


Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Linfócitos B , Transplante de Células-Tronco Hematopoéticas , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Retrospectivos , Dedos de Zinco
3.
Cancer Sci ; 111(4): 1333-1343, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32061138

RESUMO

Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN-pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN-binding proteins and mutations in these genes after Len treatment. Forty-eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post-Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN-pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post-Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fator de Transcrição Ikaros/genética , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , alfa Carioferinas/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proteínas Culina/genética , Dexametasona/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunomodulação , Lenalidomida/efeitos adversos , Masculino , Metilação , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mutação , Prognóstico , Intervalo Livre de Progressão
4.
Cancer Genet ; 242: 8-14, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32058318

RESUMO

Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy with the majority of patients being classified as B-cell lineage (B-ALL). The sub-classification of B-ALL is based on genomic architecture. Recent studies have demonstrated the capability of SNP-microarrays to detect genomic changes in B-ALL which cannot be observed by conventional cytogenetic methods. In current clinical trials, B-ALL patients at high risk of relapse are mainly identified by adverse cancer genomics and/or poor response to early therapy. To test the hypothesis that inclusion of SNP-microarrays in frontline diagnostics could more efficiently and accurately identify adverse genomic factors than conventional techniques, we evaluated the Australian high-risk B-ALL cohort enrolled on AIEOP-BFM ALL 2009 study (n = 33). SNP-microarray analysis identified additional aberrations in 97% of patients (32/33) compared to conventional techniques. This changed the genomic risk category of 24% (8/33) of patients. Additionally, 27% (9/33) of patients exhibited a 'hyperdiploid' genome, which is generally associated with a good genomic risk and favourable outcomes. An enrichment of IKZF1 deletions was observed with one third of the cohort affected. Our findings suggest the current classification system could be improved and highlights the need to use more sensitive techniques such as SNP-microarray for cytogenomic risk stratification in B-ALL.


Assuntos
Fator de Transcrição Ikaros/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Austrália , Criança , Pré-Escolar , Aberrações Cromossômicas , Bandeamento Cromossômico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Proteínas de Fusão bcr-abl/genética , Deleção de Genes , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Perda de Heterozigosidade , Masculino , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , Poliploidia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Estudos Prospectivos , Medição de Risco , Deleção de Sequência
5.
Ann Hematol ; 99(4): 809-818, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078009

RESUMO

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1plus profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1plus (n = 6/12) and B-other (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.


Assuntos
Hibridização Genômica Comparativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , RNA Mensageiro/análise , RNA Neoplásico/análise , Análise de Sequência de RNA , Cariótipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Genes Neoplásicos , Humanos , Fator de Transcrição Ikaros/genética , Hibridização in Situ Fluorescente , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prednisona/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Transcriptoma , Vincristina/administração & dosagem , Fluxo de Trabalho
7.
Chin Med J (Engl) ; 132(22): 2705-2715, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31725455

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) is a complicated condition of patients with advanced tumors. Further dissecting the microenvironment of infiltrated immune cells and malignant cells are warranted to understand the immune-evasion mechanisms of tumor development and progression. METHODS: The possible involvement of microRNAs (miRNAs) in malignant pleural fluid was investigated using small RNA sequencing. Regulatory T cell (Treg) markers (CD4, CD25, forkhead box P3), and Helios (also known as IKAROS Family Zinc Finger 2 [IKZF2]) were detected using flow cytometry. The expression levels of IKZF2 and miR-4772-3p were measured using quantitative real-time reverse transcription polymerase chain reaction. The interaction between miR-4772-3p and Helios was determined using dual-luciferase reporter assays. The effects of miR-4772-3p on Helios expression were evaluated using an in vitro system. Correlation assays between miR-4772-3p and functional molecules of Tregs were performed. RESULTS: Compared with non-malignant controls, patients with non-small cell lung cancer had an increased Tregs frequency with Helios expression in the MPE and peripheral blood mononuclear cells. The verified downregulation of miR-4772-3p was inversely related to the Helios Tregs frequency and Helios expression in the MPE. Overexpression of miR-4772-3p could inhibit Helios expression in in vitro experiments. However, ectopic expression of Helios in induced Tregs reversed the effects induced by miR-4772-3p overexpression. Additionally, miR-4772-3p could regulate Helios expression by directly targeting IKZF2 mRNA. CONCLUSION: Downregulation of miR-4772-3p, by targeting Helios, contributes to enhanced Tregs activities in the MPE microenvironment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fator de Transcrição Ikaros/metabolismo , MicroRNAs/metabolismo , Derrame Pleural Maligno/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Citometria de Fluxo , Humanos , Fator de Transcrição Ikaros/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Derrame Pleural Maligno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
BMC Med Genet ; 20(1): 159, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604453

RESUMO

BACKGROUND: Associations between IKZF1 gene variants and Acute Lymphoblastic Leukemia (ALL) was recently reported. We examined whether the common IKZF1 polymorphisms rs4132601 T/G and rs111978267 A/G are associated with ALL among a Tunisian pediatric cohort. METHODS: This case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay. RESULTS: The minor allele G of IKZF1 gene polymorphism rs4132601 T/G was significantly higher in ALL cases than in control subjects (P = 0.029), with 1.54-fold increased risk of ALL. The association of rs4132601 with ALL was seen under co-dominant (P = 0.009), recessive (P = 0.006), and additive (P = 0.027) genetic models, of which the co-dominant (P = 0.027) and recessive (P = 0.027) association remained significant after adjusting for covariates, and False Discovery Rate correction. In contrast, no association was noted for rs111978267 variant. Two-locus (rs4132601-rs11978267) IKZF1 haplotype analysis demonstrated association of GA (P = 0.053), with increased ALL risk [OR (95% CI) = 1.58 (1.00-2.51)], which remained significant after controlling for key covariates [aP = 0.046; aOR (95% CI) = 1.61 (1.01-2.57)]. CONCLUSION: We demonstrated the association of IKZF1 polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.


Assuntos
Predisposição Genética para Doença , Fator de Transcrição Ikaros/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Fatores de Risco , Tunísia
9.
Nat Immunol ; 20(11): 1517-1529, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591571

RESUMO

The establishment of a diverse B cell antigen receptor (BCR) repertoire by V(D)J recombination also generates autoreactive B cells. Anergy is one tolerance mechanism; it renders autoreactive B cells insensitive to stimulation by self-antigen, whereas Toll-like receptor (TLR) signaling can reactivate anergic B cells. Here, we describe a critical role of the transcription factor Ikaros in controlling BCR anergy and TLR signaling. Mice with specific deletion of Ikaros in mature B cells developed systemic autoimmunity. Ikaros regulated many anergy-associated genes, including Zfp318, which is implicated in the attenuation of BCR responsiveness by promoting immunoglobulin D expression in anergic B cells. TLR signaling was hyperactive in Ikaros-deficient B cells, which failed to upregulate feedback inhibitors of the MyD88-nuclear factor κB signaling pathway. Systemic inflammation was lost on expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B cells. Thus, Ikaros acts as a guardian preventing autoimmunity by promoting BCR anergy and restraining TLR signaling.


Assuntos
Autoimunidade/genética , Linfócitos B/imunologia , Anergia Clonal/genética , Fator de Transcrição Ikaros/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/imunologia , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Camundongos , Modelos Animais , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia
10.
PLoS Genet ; 15(8): e1008280, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31381561

RESUMO

One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5. These mutations often result in partial rather than complete loss of function of the transcription factor. While the functional dose of PAX5 has a clear connection to human malignancy, there is limited evidence for that heterozygote loss of PAX5 have a dramatic effect on the development and function of B-cell progenitors. One possible explanation comes from the finding that PAX5 mutated B-ALL often display complex karyotypes and additional mutations. Thus, PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to isolate proteins associated with this transcription factor in the living cell. This identified 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified the commonly mutated IKZF1 and RUNX1, involved in the formation of ETV6-AML1 fusion protein, among the interaction partners. ChIP- as well as PLAC-seq analysis supported the idea that these factors share a multitude of target genes in human B-ALL cells. Gene expression analysis of mouse models and primary human leukemia suggested that reduced function of PAX5 increased the ability of an oncogenic form of IKZF1 or ETV6-AML to modulate gene expression. Our data reveals that PAX5 belong to a regulatory network frequently targeted by multiple mutations in B-ALL shedding light on the molecular interplay in leukemia cells.


Assuntos
Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Fator de Transcrição Ikaros/genética , Camundongos , Camundongos Knockout , Mutação , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B , Cultura Primária de Células , Células Tumorais Cultivadas
11.
Genes Chromosomes Cancer ; 58(11): 815-819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31340073

RESUMO

Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high-risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome-negative B-cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD-negative after induction therapy.


Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Adulto , Biomarcadores Tumorais , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Progressão da Doença , Feminino , Deleção de Genes , Humanos , Fator de Transcrição Ikaros/metabolismo , Masculino , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Prognóstico , Recidiva
12.
Blood ; 134(15): 1227-1237, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31350265

RESUMO

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.


Assuntos
Síndrome de Down/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas de Ligação a DNA/genética , Síndrome de Down/complicações , Fator de Transcrição GATA3/genética , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Fatores de Transcrição/genética
13.
Proc Natl Acad Sci U S A ; 116(30): 15178-15183, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31285322

RESUMO

We derived a mouse model in which a mutant form of Nbn/Nbs1mid8 (hereafter Nbnmid8) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbn mid8 allele was expressed exclusively in hematopoietic lineages (in Nbn -/mid8vav mice). Unlike Nbn flox/floxvav mice with Nbn deficiency in the bone marrow, Nbn -/mid8vav mice were viable. Nbn -/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, Nbn -/mid8 mice developed highly penetrant T cell leukemias. Nbn -/mid8vav leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in NOTCH1, TP53, BCL6, BCOR, and IKZF1, suggesting that Nbn mid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn -/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1 We propose that overexpression of MRE11 compensates for the metastable Mre11-Nbnmid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.


Assuntos
Hidrolases Anidrido Ácido/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Leucêmica da Expressão Gênica , Proteína Homóloga a MRE11/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Linfócitos T/imunologia , Hidrolases Anidrido Ácido/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Medula Óssea/imunologia , Medula Óssea/patologia , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/imunologia , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Instabilidade Genômica/imunologia , Hematopoese/genética , Hematopoese/imunologia , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Proteína Homóloga a MRE11/imunologia , Camundongos , Camundongos Knockout , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/prevenção & controle , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Receptor Notch1/genética , Receptor Notch1/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Linfócitos T/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
14.
Rinsho Ketsueki ; 60(6): 708-715, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281164

RESUMO

Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.


Assuntos
Síndromes de Imunodeficiência/complicações , Transtornos Linfoproliferativos/genética , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Fator de Transcrição Ikaros/genética
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(7): 690-695, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31315770

RESUMO

OBJECTIVE: To study the clinical features of acute lymphoblastic leukemia (ALL) in children with IKAROS family zinc finger 1 (IKZF1) deletion, and to observe the effect of increasing the intensity of chemotherapy on the prognosis of this disease. METHODS: A total of 278 children diagnosed with ALL between December 2015 and February 2018 were systematically treated according to the Chinese Children's Leukemia Group-ALL 2008 protocol (CCLG-ALL 2008). The patients were divided into an IKZF1-deleted group and a control group according to the presence or absence of IKZF1. The IKZF1-deleted group was treated with the regimen for high-risk group (HR) in the CCLG-ALL 2008 protocol, while the control group received different intensities of chemotherapy according to clinical risk classification. The clinical features and event-free survival rate (EFS) were compared between the two groups. RESULTS: A total of 24 (8.6%) cases of 278 children were found to have large deletions of exons of the IKZF1 gene. The IKZF1-deleted group had significantly higher proportions of cases with white blood cell count ≥50×109/L at initial diagnosis, BCR-ABL1 fusion gene positive, minimal residual disease ≥10% on the 15th day of induction remission treatment, minimal residual disease-high risk and clinical risk classification-high risk compared with the control group (P<0.05). The 3-year EFS rate (76%±10%) in the IKZF1-deleted group was lower than that in the control group (84%±4%), but with no significant difference between the two groups (P=0.282). The estimated 3-year EFS rate in the IKZF1-deleted-non-HR group (actually treated with the chemotherapy regimen for HR in the CCLG-ALL 2008 protocol) was 82%±12%, which was lower than that in the control-non-HR group (86%±5%), but there was no significant difference (P=0.436). CONCLUSIONS: ALL children with IKZF1 deletion have worse early treatment response, and increasing the intensity of chemotherapy might improve the prognosis.


Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Intervalo Livre de Doença , Deleção de Genes , Humanos , Neoplasia Residual , Prognóstico
16.
Blood ; 134(23): 2070-2081, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31217188

RESUMO

To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.


Assuntos
Plaquetas , Doenças Genéticas Inatas , Mutação em Linhagem Germinativa , Fator de Transcrição Ikaros , Mutação de Sentido Incorreto , Trombocitopenia , Trombopoese/genética , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Cromatina/genética , Cromatina/metabolismo , Cromatina/ultraestrutura , Grânulos Citoplasmáticos/genética , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Feminino , Regulação da Expressão Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Células HEK293 , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Masculino , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia
17.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096545

RESUMO

Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.


Assuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Dineínas/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Masculino , México , Proteínas Nucleares/genética , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas de Ligação ao Cap de RNA/genética , Proteínas de Ligação a RNA/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Adulto Jovem
19.
Nat Commun ; 10(1): 1911, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015454

RESUMO

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Cadeias lambda de Imunoglobulina/genética , Mieloma Múltiplo/diagnóstico , Proteínas do Mieloma/genética , Translocação Genética , Antineoplásicos/uso terapêutico , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/imunologia , Elementos Facilitadores Genéticos , Loci Gênicos , Genoma Humano , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Plasmócitos/imunologia , Plasmócitos/patologia , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Recidiva , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Sequenciamento Completo do Genoma
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