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3.
Blood ; 134(16): 1323-1336, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31492675

RESUMO

The polycomb repressive complex 2, with core components EZH2, SUZ12, and EED, is responsible for writing histone 3 lysine 27 trimethylation histone marks associated with gene repression. Analysis of sequence data from 419 T-cell acute lymphoblastic leukemia (T-ALL) cases demonstrated a significant association between SUZ12 and JAK3 mutations. Here we show that CRISPR/Cas9-mediated inactivation of Suz12 cooperates with mutant JAK3 to drive T-cell transformation and T-ALL development. Gene expression profiling integrated with ChIP-seq and ATAC-seq data established that inactivation of Suz12 led to increased PI3K/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and WNT signaling. Moreover, a drug screen revealed that JAK3/Suz12 mutant leukemia cells were more sensitive to histone deacetylase (HDAC)6 inhibition than JAK3 mutant leukemia cells. Among the broad genome and gene expression changes observed on Suz12 inactivation, our integrated analysis identified the PI3K/mTOR, VEGF/VEGF receptor, and HDAC6/HSP90 pathways as specific vulnerabilities in T-ALL cells with combined JAK3 and SUZ12 mutations.


Assuntos
Transformação Celular Neoplásica/genética , Complexo Repressor Polycomb 2/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transdução de Sinais/fisiologia , Animais , Humanos , Janus Quinase 3/genética , Camundongos , Mutação
4.
J Immunol Res ; 2019: 5601396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346528

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common cancer among children. Recent advances in chemotherapy have made ALL a curable hematological malignancy. In children, there is 25% chance of disease relapse, typically in the central nervous system. While in adults, there is a higher chance of relapse. ALL may affect B-cell or T-cell lineages. Different genetic alterations characterize the two ALL forms. Deregulated Notch, either Notch1 or Notch3, and CXCR4 receptor signaling are involved in ALL disease development and progression. By analyzing their relevant roles in the pathogenesis of the two ALL forms, new molecular mechanisms able to modulate cancer cell invasion may be visualized. Notably, the partnership between Notch and CXCR4 may have considerable implications in understanding the complexity of T- and B-ALL. These two receptor pathways intersect other critical signals in the proliferative, differentiation, and metabolic programs of lymphocyte transformation. Also, the identification of the crosstalks in leukemia-stroma interaction within the tumor microenvironment may unveil new targetable mechanisms in disease relapse. Further studies are required to identify new challenges and opportunities to develop more selective and safer therapeutic strategies in ALL progression, possibly contributing to improve conventional hematological cancer therapy.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Receptor Notch3/genética , Receptores CXCR4/metabolismo , Adulto , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Quimiocina CXCL12/metabolismo , Criança , Progressão da Doença , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/metabolismo , Receptor Notch3/metabolismo , Transdução de Sinais/genética , Microambiente Tumoral/imunologia
5.
Nat Commun ; 10(1): 2542, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186416

RESUMO

Somatic ribosomal protein mutations have recently been described in cancer, yet their impact on cellular transcription and translation remains poorly understood. Here, we integrate mRNA sequencing, ribosome footprinting, polysomal RNA sequencing and mass spectrometry datasets from a mouse lymphoid cell model to characterize the T-cell acute lymphoblastic leukemia (T-ALL) associated ribosomal RPL10 R98S mutation. Surprisingly, RPL10 R98S induces changes in protein levels primarily through transcriptional rather than translation efficiency changes. Phosphoserine phosphatase (PSPH), encoding a key serine biosynthesis enzyme, was the only gene with elevated transcription and translation leading to protein overexpression. PSPH upregulation is a general phenomenon in T-ALL patient samples, associated with elevated serine and glycine levels in xenograft mice. Reduction of PSPH expression suppresses proliferation of T-ALL cell lines and their capacity to expand in mice. We identify ribosomal mutation driven induction of serine biosynthesis and provide evidence supporting dependence of T-ALL cells on PSPH.


Assuntos
Glicina/metabolismo , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Serina/metabolismo , Animais , Linhagem Celular , Perfilação da Expressão Gênica , Camundongos , Monoéster Fosfórico Hidrolases , Polirribossomos/genética , Polirribossomos/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Análise de Sequência de RNA
6.
PLoS Genet ; 15(6): e1008168, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199785

RESUMO

The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance.


Assuntos
Genômica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/dietoterapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Linhagem Celular Tumoral , Aberrações Cromossômicas , Evolução Clonal/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Camundongos , Mutagênese Insercional/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia
7.
Rinsho Ketsueki ; 60(5): 459-467, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31168014

RESUMO

Recent development of massive parallel-sequencing technology has revealed the genetic basis of pediatric T-cell acute lymphoblastic leukemia (T-ALL). However, epigenetic profiles of T-ALL, such as DNA methylation, have not been well characterized. To describe the epigenetic landscape of T-ALL, we investigated DNA methylation profiles of 79 cases with pediatric T-ALL by using the EPIC methylation array, which allowed us to perform more profound analyses, including the OpenSea region. Moreover, we conducted combined analyses of methylation data using our previous expression and mutation data. Based on DNA methylation profiles, pediatric T-ALL was clustered into four distinct subtypes, which exhibited remarkable association with genetic signatures and expression features, as well as profiles of normal T-cell development. Furthermore, our study revealed the importance of methylation status at binding sites of polycomb-repressive complex components and transcription factors, such as SPI1, in the classification of pediatric T-ALL based on DNA methylation status. These results might be helpful in the development of new therapeutic strategies for pediatric T-ALL.


Assuntos
Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Criança , Metilação de DNA , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Linfócitos T
8.
Blood ; 134(3): 239-251, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31076442

RESUMO

The oncogenic transcription factor TAL1 regulates the transcriptional program in T-ALL. ARID5B is one of the critical downstream targets of TAL1, which further activates the oncogenic regulatory circuit in T-ALL cells. Here, we elucidated the molecular functions of the noncoding RNA, ARID5B-inducing enhancer associated long noncoding RNA (ARIEL), in T-ALL pathogenesis. We demonstrated that ARIEL is specifically activated in TAL1 + T-ALL cases, and its expression is associated with ARID5B enhancer activity. ARIEL recruits mediator proteins to the ARID5B enhancer, promotes enhancer-promoter interactions, and activates the expression of ARID5B, thereby positively regulating the TAL1-induced transcriptional program and the MYC oncogene. The TAL1 complex coordinately regulates the expression of ARIEL Knockdown of ARIEL inhibits cell growth and survival of T-ALL cells in culture and blocks disease progression in a murine xenograft model. Our results indicate that ARIEL plays an oncogenic role as an enhancer RNA in T-ALL.


Assuntos
Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , RNA Longo não Codificante/genética , Transcrição Genética , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Elementos Facilitadores Genéticos , Técnicas de Silenciamento de Genes , Marcação de Genes , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Complexos Multiproteicos , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Fatores de Transcrição/metabolismo
9.
Pediatr Blood Cancer ; 66(9): e27829, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31136068

RESUMO

BCR-ABL1-positive leukemias have historically been classified as either chronic myelogenous leukemia or Ph+ acute lymphoblastic leukemia. Recent analyses suggest there may be a wider range of subtypes. We report a patient with BCR-ABL1 fusion positive T-cell ALL with a previously undescribed cell distribution of the fusion gene. The examination of sorted cells by fluorescence in situ hybridization showed the BCR-ABL1 fusion in the malignant T cells and a subpopulation of the nonmalignant B cells, but not nonmalignant T cells or myeloid or CD34+ progenitor cells providing evidence that the fusion may have occurred in an early lymphoid progenitor.


Assuntos
Proteínas de Fusão bcr-abl , Células Progenitoras Linfoides , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adolescente , Citometria de Fluxo , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Hibridização In Situ , Células Progenitoras Linfoides/enzimologia , Células Progenitoras Linfoides/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia
10.
Cancer Sci ; 110(6): 1931-1946, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974024

RESUMO

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.


Assuntos
Epigênese Genética , Janus Quinases/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de Transcrição STAT/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Células Jurkat , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Terapêutica com RNAi/métodos , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Mol Cancer ; 18(1): 84, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961617

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure. METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis. RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71. CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.


Assuntos
Antígenos CD/genética , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , RNA Longo não Codificante/genética , Receptores da Transferrina/genética , Fator de Transcrição STAT5/genética , Adolescente , Adulto , Animais , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Pré-Escolar , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Camundongos Nus , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores da Transferrina/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Medicine (Baltimore) ; 98(9): e14569, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817574

RESUMO

BACKGROUND: The prognostic value of microRNA (miRNA) expression in T-cell acute lymphoblastic leukemia (T-ALL) has generated significant research interest in recent years. However, most diagnostic and prognostic studies with regards to miRNA expression have been focused on combined B cell and T cell lymphoblastic leukemia. There are very few studies reporting the prognostic effects of miRNA expression on T-ALL. Therefore, a pioneer systematic review and meta-analysis was proposed to explore the possibilities of miRNAs as viable prognostic markers in T-ALL. This study is intended to be useful as a guideline for future research into drug evaluation and targeting miRNA as a biomarker for the treatment and prognosis of T-ALL. METHODS: The systematic review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The study search will be conducted by using Cochrane, EMBASE, Medline, Science Direct, and SCOPUS bibliographic databases. The reference lists of included studies will be manually searched to further bolster the search results. A combination of keywords will be used to search the databases. DISCUSSION: To explore the effect of miRNA on prognosis, forest plots will be generated to assess pooled HR and 95% CI. Upregulation, downregulation, and deregulation of specific miRNAs will be individually noted and used to extrapolate patient prognosis when associated with risk factors involved in T-ALL. Subgroup analysis will be carried out to analyze the effect of deregulation of miRNA expression on patient prognosis. A fixed or random-effects model of meta-analysis will be used depending upon between-study heterogeneity. This systematic review and meta-analysis will identify and synthesize evidence to determine the prognosis of miRNA in T-ALL and suggest the possible miRNA from meta-analysis results to predict as a biomarker for further detection and treatment of T-ALL.


Assuntos
Metanálise como Assunto , MicroRNAs/sangue , Estudos Observacionais como Assunto , Leucemia-Linfoma Linfoblástico de Células T Precursoras/sangue , Revisão Sistemática como Assunto , Biomarcadores Tumorais/sangue , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Projetos de Pesquisa , Fatores de Risco , Linfócitos T/metabolismo
13.
Ann Diagn Pathol ; 39: 53-58, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30718223

RESUMO

The transmembrane receptor NOTCH1 is thought to be associated with the development and progression of T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma (T-LBL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The current study aimed to characterize NOTCH1 expression and elucidate the variants in the functional PEST domain of the receptor in T-ALL/LBL and CLL/SLL. The nuclear expression of NOTCH1 protein was detected in 25% and 5% of cases of T-ALL/LBL and CLL/SLL, respectively, whereas cytoplasmic expression was detected in 33.3% and 15% cases, respectively. The frequency of variants in T-ALL/LBL was 33%, whereas 40% of CLL/SLL cases possessed variants. Four novel variants were identified; three of which were non-synonymous and one common variant c.7280_7280delG between T-ALL/LBL and CLL/SLL cases. The previously described variant, c.7541_7542delCT, was detected in 3 cases of CLL/SLL. These results provide support for the contribution of NOTCH1 in the etiology of these types of cancers.


Assuntos
Variação Genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Jordânia , Masculino , Domínios Proteicos , Receptor Notch1/química
14.
Oncogene ; 38(23): 4620-4636, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30742097

RESUMO

FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, ß and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7ß isoform and to a lesser extent FBXW7α and may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs. Transient transfections with miRNA mimics in selected cell lines resulted in a significant decrease of total FBXW7 expression and its different isoforms separately, with the consequent increment of critical substrates and the stimulation of cell proliferation. Transient inhibition of endogenous miRNAs in a T-cell lymphoblastic-derived cell line (SUP-T1) was capable of reversing these proliferative effects. Finally, we show how FBXW7 isoforms display different roles within the cell. Simultaneous downregulation of the α and γ isoforms modulates the amount of CCNE1, whilst the ß-isoform alone was found to have a prominent role in modulating the amount of c-MYC. Our data also revealed that downregulation of all isoforms is a sine qua non condition to induce a proliferative pattern in our cell model system. Taking these data into account, potential new treatments to reverse downregulation of all or a specific FBXW7 isoform may be an effective strategy to counteract the proliferative capacity of these tumour cells.


Assuntos
Proteína 7 com Repetições F-Box-WD/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Isoenzimas/genética , Células Jurkat , MicroRNAs/genética , Análise em Microsséries , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia
15.
Leukemia ; 33(8): 1868-1880, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30700838

RESUMO

T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. While it has been shown that TAL1/LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2/Lyl1; however, NHD13 can also promote T-ALL via an alternative pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Proteínas de Homeodomínio/genética , Proteínas com Domínio LIM/fisiologia , Proteínas de Neoplasias/fisiologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Timócitos/fisiologia , Fatores de Transcrição/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
16.
Cancer Genet ; 231-232: 1-13, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803551

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is not as frequently reported as the B-cell counterpart (B-ALL), only occurring in about 15% of pediatric cases with a typically heterogeneous etiology. Approximately 8% of childhood T-ALL cases have rearrangements involving the ABL1 tyrosine kinase gene at 9q34.12; although a t(9;22), resulting in a fusion of ABL1 with the BCR gene at 22q11.23 is a common occurrence in B-ALL, it is not a typical finding in T-ALL. A subset of 10 of 40 documented cases of T-ALL analyzed over a 5-year period is presented, each having gene rearrangements within band 9q34 that resulted in fusions other than BCR/ABL1. These cases included fusions involving ABL1, SET (9q34.11), NUP214 (9q34.13), SPTAN1 (9p34.11), and TNRC6B (22q13.1). Among the 10 cases are: six SET/NUP214 fusions, two ABL1/NUP214 fusions (one of which was associated with episomal amplification) and novel SPTAN1/ABL1 and TNRC6B/ABL1 fusions. The evaluations of these clones were each significantly aided by FISH analysis, which directed subsequent microarray and anchored multiplex PCR testing for fusion confirmations.


Assuntos
Cromossomos Humanos Par 9/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Criança , Pré-Escolar , Humanos
17.
Neoplasia ; 21(3): 294-310, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30763910

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles. To extend miRNome characteristics in T-ALL (to 82 T-ALL cases), we combined our small RNA-seq results with data available in Gene Expression Omnibus. We report on miRNAs most abundantly expressed in pediatric T-ALL and miRNAs differentially expressed in T-ALL versus normal mature T-lymphocytes and thymocytes, representing candidate oncogenic and tumor suppressor miRNAs. Using eight target prediction algorithms and pathway enrichment analysis, we identified differentially expressed miRNAs and their predicted targets implicated in processes (defined in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of potential importance in pathogenesis of T-ALL, including interleukin-6-mediated signaling, mTOR signaling, and regulation of apoptosis. We finally focused on hsa-mir-106a-363 cluster and functionally validated direct interactions of hsa-miR-20b-5p and hsa-miR-363-3p with 3' untranslated regions of their predicted targets (PTEN, SOS1, LATS2), overrepresented in regulation of apoptosis. hsa-mir-106a-363 is a paralogue of prototypic oncogenic hsa-mir-17-92 cluster with yet unestablished role in the pathogenesis of T-ALL. Our study provides a firm basis and data resource for functional analyses on the role of miRNA-mRNA interactions in T-ALL.


Assuntos
Regulação Leucêmica da Expressão Gênica , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Interferência de RNA , RNA Mensageiro/genética , Transcriptoma , Apoptose/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Genes Reporter , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico
18.
BMC Med Genomics ; 12(1): 8, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30646895

RESUMO

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Aberrant expressed genes contribute to the development and progression of T-ALL. However, the regulation underlying their aberrant expression remains elusive. Dysregulated expression of transcription factors and miRNAs played important regulatory roles in the pathogenesis of T-ALL. METHODS: In this study, we analyzed the alteration of transcriptome profiling and regulatory networks between T-ALL sample and normal T cell samples at transcriptional and post-transcriptional levels. RESULTS: Our results demonstrated that genes related to cell cycle and cell proliferation processes were significantly upregulated in T-ALL comparing to normal samples. Meanwhile, regulatory network analyses revealed that FOXM1, MYB, SOX4 and miR-21/19b as core regulators played vital roles in the development of T-ALL. FOXM1-miR-21-5p-CDC25A and MYB/SOX4-miR-19b-3p-RBBP8 were identified as important feed-forward loops involved in the oncogenesis of T-ALL. Drug-specific analyses showed that GSK-J4 may be an effective drug, and CDC25A/CAPN2/MCM2 could serve as potential therapeutic targets for T-ALL. CONCLUSIONS: This study may provide novel insights for the regulatory mechanisms underlying the development of T-ALL and potential therapeutic targets.


Assuntos
Carcinogênese/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia
19.
J Immunol ; 202(4): 1137-1144, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30651344

RESUMO

Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to T-ALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e., Rag2 - / - γc - / -, γc - / -, Rag2 - / - IL-7rα - / -, and IL-7rα - / - We found that the cellularity of the thymus grafts is influenced exclusively by the genotype of the host, i.e., IL-7rα-/- versus γc -/- Nonetheless, the difference in cellularity detected in thymus autonomy bore no impact on onset, incidence, immunophenotype, or pathologic condition of T-ALL. In all tested conditions, T-ALL reached an incidence of 80%, demonstrating that thymus autonomy bears a high risk of leukemia. We also analyzed the microbiota composition of the recipients and their genetic background, but none of the differences found influenced the development of T-ALL. Taken together, our data support that IL-7 drives cellular turnover non-cell autonomously, which is required for prevention of T-ALL. We found no influence for T-ALL in the specific combination of the genotypic mutations tested (including the developmental block caused by Rag deficiency), in microbiota composition, or minor differences in the genetic background of the strains.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Receptores de Interleucina-7/imunologia , Timo/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética
20.
Am J Hematol ; 94(4): E93-E96, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30614545
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