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1.
Blood ; 140(17): 1875-1890, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-35839448

RESUMO

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.


Assuntos
Proteína de Leucina Linfoide-Mieloide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Genes Reguladores , Cromatina
2.
Blood ; 119(1): 196-205, 2012 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22084312

RESUMO

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.


Assuntos
Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Receptor fas/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , DNA de Neoplasias/genética , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Leucemia Promielocítica Aguda/tratamento farmacológico , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , RNA Interferente Pequeno/genética , Indução de Remissão , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
3.
JCI Insight ; 8(2)2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36480300

RESUMO

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.


Assuntos
Dioxigenases , Leucemia Mieloide Aguda , Humanos , Camundongos , Animais , Azacitidina , Leucemia Mieloide Aguda/genética , Estimativa de Kaplan-Meier , Mutação , Proteínas de Ligação a DNA/genética , Dioxigenases/genética
4.
Nat Commun ; 12(1): 665, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510140

RESUMO

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10-9) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10-8), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Idoso , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Locos de Características Quantitativas/genética
5.
Nat Commun ; 12(1): 6233, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34716350

RESUMO

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).


Assuntos
Antígenos HLA/genética , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Aldeído Redutase/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , População Branca/genética
6.
Blood Adv ; 2(10): 1157-1169, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789314

RESUMO

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Nucleosídeos/metabolismo , Ribonucleotídeo Redutases/genética , Idoso , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Pessoa de Meia-Idade
8.
Eur Urol ; 64(5): 753-61, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23582880

RESUMO

BACKGROUND: Primary culture and animal and cell-line models of prostate and bladder development have limitations in describing human biology, and novel strategies that describe the full spectrum of differentiation from foetal through to ageing tissue are required. Recent advances in biology demonstrate that direct reprogramming of somatic cells into pluripotent embryonic stem cell (ESC)-like cells is possible. These cells, termed induced pluripotent stem cells (iPSCs), could theoretically generate adult prostate and bladder tissue, providing an alternative strategy to study differentiation. OBJECTIVE: To generate human iPSCs derived from normal, ageing, human prostate (Pro-iPSC), and urinary tract (UT-iPSC) tissue and to assess their capacity for lineage-directed differentiation. DESIGN, SETTING, AND PARTICIPANTS: Prostate and urinary tract stroma were transduced with POU class 5 homeobox 1 (POU5F1; formerly OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel-like factor 4 (gut) (KLF4), and v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) genes to generate iPSCs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used. RESULTS AND LIMITATIONS: Successful reprogramming of prostate tissue into Pro-iPSCs and bladder and ureter into UT-iPSCs was demonstrated by characteristic ESC morphology, marker expression, and functional pluripotency in generating all three germ-layer lineages. In contrast to conventional skin-derived iPSCs, Pro-iPSCs showed a vastly increased ability to generate prostate epithelial-specific differentiation, as characterised by androgen receptor and prostate-specific antigen induction. Similarly, UT-iPSCs were shown to be more efficient than skin-derived iPSCs in undergoing bladder differentiation as demonstrated by expression of urothelial-specific markers: uroplakins, claudins, and cytokeratin; and stromal smooth muscle markers: α-smooth-muscle actin, calponin, and desmin. These disparities are likely to represent epigenetic differences between individual iPSC lines and highlight the importance of organ-specific iPSCs for tissue-specific studies. CONCLUSIONS: IPSCs provide an exciting new model to characterise mechanisms regulating prostate and bladder differentiation and to develop novel approaches to disease modelling. Regeneration of bladder cells also provides an exceptional opportunity for translational tissue engineering.


Assuntos
Diferenciação Celular , Linhagem da Célula , Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/fisiologia , Próstata/fisiologia , Regeneração , Engenharia Tecidual/métodos , Ureter/fisiologia , Bexiga Urinária/fisiologia , Idoso , Biomarcadores/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Separação Celular , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Calicreínas/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Pessoa de Meia-Idade , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Próstata/citologia , Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Androgênicos/metabolismo , Regeneração/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Tempo , Transfecção , Ureter/citologia , Ureter/metabolismo , Bexiga Urinária/citologia , Bexiga Urinária/metabolismo , Uroplaquinas/metabolismo
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