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1.
Mol Cell ; 81(16): 3323-3338.e14, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352207

RESUMO

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m7G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.


Assuntos
Carcinogênese/genética , Metiltransferases/genética , Neoplasias/genética , tRNA Metiltransferases/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Metilação , Neoplasias/patologia , Oncogenes/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
2.
Blood Adv ; 5(9): 2412-2425, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33956058

RESUMO

Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD-positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beauty transposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), and Runx1 (5/38). Insertions at Setbp1 led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1 was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1 expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1 overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+ AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.


Assuntos
Leucemia Mieloide Aguda , Doença Aguda , Animais , Proteínas de Ligação a DNA , Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda/genética , Camundongos , Mutação , Proteínas Nucleares/genética
3.
Nature ; 593(7860): 597-601, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33902106

RESUMO

N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy.

4.
Leukemia ; 35(4): 1012-1022, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32764680

RESUMO

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis, and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.


Assuntos
Rearranjo Gênico , Predisposição Genética para Doença , Histona Acetiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Apoptose/genética , Biomarcadores Tumorais , Diferenciação Celular , Linhagem Celular Tumoral , Gerenciamento Clínico , Epigênese Genética , Técnicas de Inativação de Genes , Estudos de Associação Genética , Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Células Mieloides/metabolismo , Células Mieloides/patologia , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica
5.
Nat Commun ; 11(1): 4132, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807781

RESUMO

Precise genome editing using CRISPR-Cas9 is a promising therapeutic avenue for genetic diseases, although off-target editing remains a significant safety concern. Guide RNAs shorter than 16 nucleotides in length effectively recruit Cas9 to complementary sites in the genome but do not permit Cas9 nuclease activity. Here we describe CRISPR Guide RNA Assisted Reduction of Damage (CRISPR GUARD) as a method for protecting off-targets sites by co-delivery of short guide RNAs directed against off-target loci by competition with the on-target guide RNA. CRISPR GUARD reduces off-target mutagenesis while retaining on-target editing efficiencies with Cas9 and base editor. However, we discover that short guide RNAs can also support base editing if they contain cytosines within the deaminase activity window. We explore design rules and the universality of this method through in vitro studies and high-throughput screening, revealing CRISPR GUARD as a rapidly implementable strategy to improve the specificity of genome editing for most genomic loci. Finally, we create an online tool for CRISPR GUARD design.


Assuntos
Edição de Genes/métodos , RNA Guia/metabolismo , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/fisiologia , Humanos , Mutagênese/genética , Mutagênese/fisiologia , RNA Guia/genética
6.
Nat Commun ; 9(1): 5378, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568163

RESUMO

We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.


Assuntos
Leucemia Mieloide Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular , Diferenciação Celular , Cromatina/metabolismo , Epigênese Genética , Células HL-60 , Hematopoese , Humanos , Células K562 , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Splicing de RNA
7.
Cell Stem Cell ; 23(5): 700-713.e6, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388424

RESUMO

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Células Clonais/efeitos dos fármacos , Doxorrubicina/farmacologia , Hematopoese/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Proteína Fosfatase 2C/genética , Idoso , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HEK293 , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteína Fosfatase 2C/metabolismo
8.
EMBO Mol Med ; 10(10)2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30190333

RESUMO

Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c-Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.


Assuntos
Neoplasias da Mama/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Metástase Neoplásica/fisiopatologia , Transdução de Sinais , Animais , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Feminino , Xenoenxertos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Transplante de Neoplasias , Células-Tronco Neoplásicas/fisiologia
9.
Nat Genet ; 50(6): 883-894, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736013

RESUMO

The histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings identify a dual role for UTX in suppressing acute myeloid leukemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.


Assuntos
Cromatina/genética , Elementos Facilitadores Genéticos , Fatores de Transcrição GATA/genética , Histona Desmetilases/genética , Leucemia Mieloide/genética , Proteínas Proto-Oncogênicas c-ets/genética , Animais , Linhagem Celular , Montagem e Desmontagem da Cromatina/genética , Regulação Leucêmica da Expressão Gênica , Células HEK293 , Histonas/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteômica/métodos , Sequências Reguladoras de Ácido Nucleico/genética , Ativação Transcricional
10.
Nature ; 552(7683): 126-131, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29186125

RESUMO

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.


Assuntos
Adenosina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Metiltransferases/metabolismo , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas , Adenosina/genética , Adenosina/metabolismo , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromatina/genética , Cromatina/metabolismo , Feminino , Genes Neoplásicos/genética , Humanos , Leucemia Mieloide Aguda/patologia , Metiltransferases/química , Metiltransferases/deficiência , Metiltransferases/genética , Camundongos , Biossíntese de Proteínas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Sítio de Iniciação de Transcrição
11.
Leuk Lymphoma ; 58(2): 257-265, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27401303

RESUMO

The p15 gene (also known as CDKN2B, INK4B, p15INK4B), located in band 9p21, encodes a protein that induces a G1-phase cell cycle arrest through inhibition of CDK4/6 (cyclin-dependent kinase 4/6). It also plays an important role in the regulation of cellular commitment of hematopoietic progenitor cells and myeloid cell differentiation. p15 can be silenced by several mechanisms, including deletion and hypermethylation of its promoter. Homozygous p15 deletion is rare in acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS) but frequent in acute lymphoblastic leukemia (ALL). On the contrary, methylation of the p15 promoter is identified in some 50% of the patients with AML and MDS, but is less frequent in ALL. The analysis of the 28 studies available in the literature revealed conflicting results (unfavorable, favorable or no impact) that can be due, at least in part, to methodological and/or biological pitfalls. Among those, are the heterogeneity of the methylation patterns of the p15 gene and the lack of a comprehensive analysis including transcriptional and translational inactivation that have major impact on its expression. Therefore, detection of the p15 mRNA expression (quantitative or not) may represent a more appropriate method to determine the prognostic impact of the p15 gene.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Variação Genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Inibidor de Quinase Dependente de Ciclina p15/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico
12.
Methods Mol Biol ; 1541: 311-331, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27910033

RESUMO

The main databases devoted stricto sensu to cancer cytogenetics are the "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer" ( http://cgap.nci.nih.gov/Chromosomes/Mitelman ), the "Atlas of Genetics and Cytogenetics in Oncology and Haematology" ( http://atlasgeneticsoncology.org ), and COSMIC ( http://cancer.sanger.ac.uk/cosmic ).However, being a complex multistep process, cancer cytogenetics are broadened to "cytogenomics," with complementary resources on: general databases (nucleic acid and protein sequences databases; cartography browsers: GenBank, RefSeq, UCSC, Ensembl, UniProtKB, and Entrez Gene), cancer genomic portals associated with recent international integrated programs, such as TCGA or ICGC, other fusion genes databases, array CGH databases, copy number variation databases, and mutation databases. Other resources such as the International System for Human Cytogenomic Nomenclature (ISCN), the International Classification of Diseases for Oncology (ICD-O), and the Human Gene Nomenclature Database (HGNC) allow a common language.Data within the scientific/medical community should be freely available. However, most of the institutional stakeholders are now gradually disengaging, and well-known databases are forced to beg or to disappear (which may happen!).


Assuntos
Biologia Computacional/métodos , Citogenética/métodos , Bases de Dados Genéticas , Navegador , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Análise Citogenética/métodos , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , Software , Interface Usuário-Computador
13.
Cell Rep ; 17(4): 1193-1205, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27760321

RESUMO

Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Testes Genéticos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular , Adulto , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , Reprodutibilidade dos Testes
14.
Expert Rev Anticancer Ther ; 15(9): 1093-102, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26211807

RESUMO

In 1963, Jean Bernard, a French hematologist, opened a new chapter in hematology called geographic hematology ('Hématologie Géographique'). He distinguished two research avenues. One dealt with the differences between the various populations (ethnic hematology), the other with various environmental factors (environmental hematology). In recent years, focus has been put on analyzing the genetic susceptibility in cancer and hematological malignancies, particularly in childhood acute lymphoblastic leukemia, using specific gene or (genome-wide association study) approach. However, almost 30 years ago, it was suggested by a few workers that chromosomal abnormalities observed in leukemia could have a geographic and/or ethnic distribution. In this review, we analyze the literature on chromosomal and molecular abnormalities in several types of leukemia.


Assuntos
Predisposição Genética para Doença , Leucemia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Aberrações Cromossômicas , Estudo de Associação Genômica Ampla , Humanos , Leucemia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
15.
Future Oncol ; 11(11): 1675-86, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26043219

RESUMO

The EVI1 gene, located in chromosomal band 3q26, is a transcription factor that has stem cell-specific expression pattern and is essential for the regulation of self-renewal of hematopoietic stem cells. It is now recognized as one of the dominant oncogenes associated with myeloid leukemia. EVI1 overexpression is associated with minimal to no response to chemotherapy and poor clinical outcome. Several chromosomal rearrangements involving band 3q26 are known to induce EVI1 overexpression. They are mainly found in acute myeloid leukemia and blastic phase of Philadelphia chromosome-positive chronic myeloid leukemia, more rarely in myelodysplastic syndromes. They include inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(3;12)(q26;p13) and t(2;3)(p15-23;q26). However, many other chromosomal rearrangements involving 3q26/EVI1 have been identified. The precise molecular event has not been elucidated in the majority of these chromosomal abnormalities and most gene partners remain unknown.


Assuntos
Proteínas de Ligação a DNA/genética , Rearranjo Gênico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Proto-Oncogenes/genética , Fatores de Transcrição/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 3 , Expressão Gênica , Humanos , Proteína do Locus do Complexo MDS1 e EVI1
17.
Expert Rev Hematol ; 7(3): 347-57, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24720386

RESUMO

The t(15;17)(q24;q21), generating a PML-RARA fusion gene, is the hallmark of acute promyelocytic leukemia (APL). At present, eight other genes fusing with RARA have been identified. The resulting fusion proteins retain domains of the RARA protein allowing binding to retinoic acid response elements (RARE) and dimerization with the retinoid X receptor protein (RXRA). They participate in protein-protein interactions, associating with RXRA to form hetero-oligomeric complexes that can bind to RARE. They have a dominant-negative effect on wild-type RARA/RXRA transcriptional activity. Moreover, RARA fusion proteins can homodimerize, conferring the ability to regulate an expanded repertoire of genes normally not affected by RARA. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of ATRA or arsenic trioxide. However, resistance to these two drugs is a major problem, which necessitates development of new therapies.


Assuntos
Fusão Gênica , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Receptores do Ácido Retinoico/genética , Animais , Diferenciação Celular/genética , Aberrações Cromossômicas , Humanos , Leucemia Promielocítica Aguda/patologia , Elementos de Resposta , Receptor alfa de Ácido Retinoico
18.
Future Oncol ; 10(3): 475-95, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24559452

RESUMO

In humans, class I homeobox genes (HOX genes) are distributed in four clusters. Upstream regulators include transcriptional activators and members of the CDX family of transcription factors. HOX genes encode proteins and need cofactor interactions, to increase their specificity and selectivity. HOX genes contribute to the organization and regulation of hematopoiesis by controlling the balance between proliferation and differentiation. Changes in HOX gene expression can be associated with chromosomal rearrangements generating fusion genes, such as those involving MLL and NUP98, or molecular defects, such as mutations in NPM1 and CEBPA for example. Several miRNAs are involved in the control of HOX gene expression and their expression correlates with HOX gene dysregulation. HOX genes dysregulation is a dominant mechanism of leukemic transformation. A better knowledge of their target genes and the mechanisms by which their dysregulated expression contributes to leukemogenesis could lead to the development of new drugs.


Assuntos
Regulação Leucêmica da Expressão Gênica , Genes Homeobox , Leucemia Mieloide Aguda/genética , Animais , Genes Neoplásicos , Humanos , Leucemia Mieloide Aguda/metabolismo , Família Multigênica , Proteínas de Fusão Oncogênica/genética
19.
Expert Rev Mol Diagn ; 14(2): 127-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24437978

RESUMO

Since the first specific chromosomal abnormality was identified in leukemia more than 50 years ago, technology has much evolved, now allowing the deciphering of cancer genomes in ever-greater detail. However, much has still to be learned as we have not yet completely dissected all the genomic aberrations driving the genesis and the evolution of malignant hemopathies. The first techniques that have been developed allowed 'gross' chromosomal abnormalities to be identified. They include conventional and molecular cytogenetics and microarray-based techniques. However, these techniques can only reveal part of the problem, as genes can be altered in a number of ways (mutations, methylation and so on). This led to the development of what is now known as next-generation sequencing (NGS). Each method has advantages and limits. At present, no single method can decipher all the mechanisms involved in leukemogenesis. Therefore, in our view, it is unlikely that a particular technique will become the 'gold standard'.


Assuntos
Análise Citogenética/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia/diagnóstico , Leucemia/genética , Análise Citogenética/tendências , Metilação de DNA , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Hibridização in Situ Fluorescente , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Transcriptoma
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