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2.
J Med Chem ; 61(22): 10299-10309, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30365892

RESUMO

Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.

3.
Mol Cell Oncol ; 5(4): e1497860, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250933

RESUMO

Genetic lineage tracing in cell type-specific mouse models of T-cell acute lymphoblastic leukemia (T-ALL) have revealed that tumor cell identity is imposed by expression of the oncogene Lim Domain Only 2 (LMO2), rather than by the target cell phenotype. This approach allowed to identify that secondary genomic alterations, like Notch1 mutations, appeared late and only took place within the thymus during T-ALL development. These concepts are therefore critical for the development of modern therapies aimed at curing T-ALL.

4.
Haematologica ; 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093397

RESUMO

The homeobox gene HLXB9 encodes for the transcription factor HB9, which is essential for pancreatic as well as motor neuronal development. Beside its physiologic expression pattern, aberrant HB9 expression has been observed in several neoplasias. Especially in infant translocation t(7;12) acute myeloid leukemia aberrant HB9 expression is the only known molecular hallmark and assumed to be a key factor in leukemic transformation. However, up to now only poor functional data exist addressing the oncogenic potential of HB9 or its influence on hematopoiesis. We investigated the influence of HB9 on cell proliferation and cell cycle in vitro, as well as on hematopoietic stem cell differentiation in vivo using murine and human model systems. In vitro, HB9 expression led to premature senescence in human HT1080 and murine NIH3T3 cells, providing for the first time evidence for an oncogenic potential of HB9. Onset of senescence was characterized by induction of the p53-p21 tumor suppressor network, resulting in growth arrest, accompanied by morphological transformation and expression of senescence-associated ß-galactosidase. In vivo, HB9-transduced primary murine hematopoietic stem and progenitor cells underwent a profound differentiation arrest and accumulated at the megakaryocyte/erythrocyte progenitor stage. In line, gene expression analyses revealed de novo expression of erythropoiesis-related genes in human CD34+ hematopoietic stem and progenitor cells upon HB9 expression. In summary, the novel findings of HB9 dependent premature senescence and myeloid-biased perturbed hematopoietic differentiation shed light on the oncogenic properties of HB9 in translocation t(7;12) acute myeloid leukemia for the first time.

5.
Trends Cancer ; 4(6): 408-417, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29860985

RESUMO

Recent evidence from hematopoietic and epithelial tumors revealed that the contribution of oncogenes to cancer development is mediated mainly through epigenetic priming of cancer-initiating cells, suggesting that genetic lesions that initiate the cancer process might be dispensable for the posterior tumor progression and maintenance. Epigenetic priming may remain latent until it is later triggered by endogenous or environmental stimuli. This Opinion article addresses the impact of epigenetic priming in cancer development and in the design of new therapeutic approaches.

6.
EMBO J ; 37(14)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-29880602

RESUMO

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.

7.
Blood ; 132(3): 307-320, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-29724897

RESUMO

Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.

8.
Cancer Res ; 78(10): 2669-2679, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29490943

RESUMO

Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. ©2018 AACR.

9.
Oncotarget ; 8(60): 102674-102680, 2017 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-29254279

RESUMO

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. Pre-leukaemic clones carrying ETV6-RUNX1 oncogenic lesions are frequently found in neonatal cord blood, but only few ETV6-RUNX1 carriers develop pB-ALL. The highly demanding and pending challenge is to reveal the multistep natural history of ETV6-RUNX1 pB-ALL, because it can offer non-toxic prophylactic interventions to preleukemic carriers. However, the lack of a genetically engineered ETV6-RUNX1 mouse model mimicking the human pB-ALL has hampered our understanding of the pathogenesis of this disease. This rule has now been broken in a study of the effect of the ETV6-RUNX1 oncogene in cancer development in a mouse model in which oncogene expression is restricted to the stem cell compartment. In this article, we review the different attempts to model this disease, including the recent representative success stories and we discuss its potential application to both identify etiologic factors of childhood ETV6-RUNX1 pB-ALL and prevent the conversion of a preleukemic clone in an irreversible transformed state.

10.
Oncotarget ; 8(44): 75797-75807, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100269

RESUMO

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in mature B-cells, while AID was also shown to play a role in developing pre-BCR/BCR-positive B-cells of the bone marrow. To further elucidate a potential function of Aid in the bone marrow prior to V(D)J-recombination, we utilized an in vivo model which exerts a B-cell developmental arrest at the pro-B cell stage with low frequencies of pro-B cell acute lymphoblastic leukemia (pro-B ALL) development. Therefore, p19Arf-/-Rag1-/- (AR) mice were crossed with Aid-deficient mice (ARA). Surprisingly, loss of Aid expression in pro-B cells accelerated pro-B ALL incidence from 30% (AR) to 98% (ARA). This effect was Aid dose dependent, since Aid+/- animals of the same background displayed a significantly lower incidence (83%). Furthermore, B-cell-specific Aid up-regulation was observed in Aid-competent pro-B ALLs. Additional whole exome/sanger sequencing of murine pro-B ALLs revealed an accumulation of recurrent somatic Jak3 (p.R653H, p.V670A) and Dnm2 (p.G397R) mutations, which highlights the importance of active IL7R signaling in the pro-B ALL blast cells. These findings were further supported by an enhanced proliferative potential of ARA pro-B cells compared to Aid-competent cells from the same genetic background. In summary, we show that both Aid and Rag1 act as a negative regulators in pro-B cells, preventing pro-B ALL.

11.
Cancer Res ; 77(16): 4365-4377, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28630052

RESUMO

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365-77. ©2017 AACR.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Histona Desmetilases/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/microbiologia , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética
12.
Am J Med Genet A ; 173(4): 1017-1037, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28168833

RESUMO

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.


Assuntos
Predisposição Genética para Doença , Neoplasias Hematológicas/diagnóstico , Mutação , Proteínas de Neoplasias/genética , Neoplasias/diagnóstico , Adolescente , Criança , Grupos Focais/métodos , Expressão Gênica , Aconselhamento Genético/ética , Testes Genéticos/métodos , Genética Médica/história , Genética Médica/instrumentação , Genética Médica/métodos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , História do Século XXI , Humanos , Neoplasias/genética , Neoplasias/patologia , Sociedades Médicas/história , Síndrome
14.
Expert Opin Drug Discov ; 11(11): 1081-1091, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27562952

RESUMO

INTRODUCTION: The development of novel drugs which specifically target leukemic cells, with the overall aim to increase complete remission and to reduce toxicity and morbidity, is the most important prerequisite for modern leukemia treatment. In this regard, the current transition rate of potential novel drugs from bench to bedside is remarkably low. Although many novel drugs show promising data in vitro and in vivo, testing of these medications in clinical phase I trials is often sobering with intolerable toxic side effects leading to failure in FDA approval. Areas covered: In this review, the authors discuss the development of murine model generation in the context of targeted therapy development for the treatment of childhood leukemia, aiming to decrease the attrition rate of progressively complex targeted therapies ranging from small molecules to cell therapy. As more complex therapeutic approaches develop, more complex murine models are needed, to recapitulate closely the human phenotype. Expert opinion: Combining xenograft models for efficacy testing and GEMMs for toxicity testing will be a global approach for pre-clinical testing of complex therapeutics and will contribute to the clinical approval of novel compounds. Finally, this approach is likely to increase clinical approval of novel compounds.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Leucemia/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Criança , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Leucemia/patologia , Camundongos , Terapia de Alvo Molecular , Especificidade da Espécie , Testes de Toxicidade/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Eur J Med Genet ; 59(3): 166-72, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26626503

RESUMO

Germline mutations in transcription factors, which are implicated in hematopoiesis in general or specifically in B-cell differentiation have recently been described to confer an inherited risk to pB-ALL with often reduced penetrance. Predicting leukemia development, therapy response and long term follow up of mutation carriers is challenging because experience from large patient cohorts and their long term follow up are not available. Genetically Engineered Murine Models (GEMMs) represent a promising approach to create individualized and precise models reproducing the molecular makeup of the human disease. This review focuses on PAX5 loss-of-function and summarizes techniques of murine model generation, available GEMMs, which mimic Pax5 loss-of-function in leukemia development and discusses the challenges and drawbacks of these models. These aspects are discussed in the context of creating a robust model, which serves not only for validation of the relevance of a genomic alteration in pB-ALL but at the same time as a valid preclinical model.


Assuntos
Modelos Animais de Doenças , Predisposição Genética para Doença , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Fatores Etários , Animais , Marcação de Genes , Humanos , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX5/metabolismo , Penetrância , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
17.
Cancer Discov ; 5(12): 1328-43, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26408659

RESUMO

UNLABELLED: Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5(+/-) leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development. SIGNIFICANCE: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease.


Assuntos
Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiologia , Animais , Transplante de Medula Óssea , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Análise por Conglomerados , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Exoma , Feminino , Perfilação da Expressão Gênica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Interleucina-7/metabolismo , Interleucina-7/farmacologia , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/genética , Masculino , Camundongos , Camundongos Knockout , Mutação , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Interleucina-7/genética , Fator de Transcrição STAT5/genética , Integração Viral
18.
Semin Cancer Biol ; 32: 3-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24530939

RESUMO

Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumor cells. However, recent evidences have revealed that cancer stem cells could arise through a tumor stem cell reprogramming mechanism, suggesting that genetic lesions that initiate the cancer process might be dispensable for tumor progression and maintenance. This review addresses the impact of these results toward a better understanding of cancer development and proposes new approaches to treat cancer in the future.


Assuntos
Transformação Celular Neoplásica/genética , Reprogramação Celular/genética , Neoplasias/genética , Células-Tronco Neoplásicas , Oncogenes/genética , Animais , Diferenciação Celular/genética , Modelos Animais de Doenças , Humanos , Camundongos , Modelos Biológicos , Neoplasias/terapia
19.
Cell Cycle ; 13(18): 2836-46, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25486471

RESUMO

B-cell precursor acute lymphoblastic leukemias (pB-ALLs) are the most frequent type of malignancies of the childhood, and also affect an important proportion of adult patients. In spite of their apparent homogeneity, pB-ALL comprises a group of diseases very different both clinically and pathologically, and with very diverse outcomes as a consequence of their biology, and underlying molecular alterations. Their understanding (as a prerequisite for their cure) will require a sustained multidisciplinary effort from professionals coming from many different fields. Among all the available tools for pB-ALL research, the use of animal models stands, as of today, as the most powerful approach, not only for the understanding of the origin and evolution of the disease, but also for the development of new therapies. In this review we go over the most relevant (historically, technically or biologically) genetically engineered mouse models (GEMMs) of human pB-ALLs that have been generated over the last 20 years. Our final aim is to outline the most relevant guidelines that should be followed to generate an "ideal" animal model that could become a standard for the study of human pB-ALL leukemia, and which could be shared among research groups and drug development companies in order to unify criteria for studies like drug testing, analysis of the influence of environmental risk factors, or studying the role of both low-penetrance mutations and cancer susceptibility alterations.


Assuntos
Modelos Animais de Doenças , Engenharia Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Animais , Humanos , Camundongos , Transdução Genética , Translocação Genética , Transplante Heterólogo
20.
Hum Mol Genet ; 23(3): 590-601, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24045615

RESUMO

Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls.


Assuntos
Proteínas de Transporte/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recombinases/genética , Recombinação V(D)J , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Deleção de Genes , Humanos , Lactente , Masculino , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T
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