RESUMO
The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.
Assuntos
Processamento Alternativo , Proteínas de Ligação a DNA/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/mortalidade , Modelos Biológicos , Proteínas Nucleares/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Adolescente , Adulto , Idoso , Criança , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Modelos de Riscos Proporcionais , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Taxa de Sobrevida , Proteína Tumoral p73 , Proteínas Supressoras de Tumor/genéticaAssuntos
COVID-19 , Leucemia Mieloide Aguda , Adulto , Brasil/epidemiologia , Humanos , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Promielocítica Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idoso , Animais , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Masculino , Microdomínios da Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
We retrospectively studied the outcomes of adults with de novo acute myeloid leukemia treated in a reference center in Brazil and analyzed the association with the human development index (HDI) of the United Nations used as a socioeconomic factor. Among 123 patients, 46 (37%) died during induction, 65 (53%) reached complete remission and 45 (37%) received high-dose cytarabine (Hidac) consolidation. The 5-year overall survival and leukemia-free survival (LFS) were 17 and 26%, respectively, for all patients and 36 and 30%, respectively, for those receiving Hidac. In multivariate analysis, an HDI <0.660 was associated with a lower probability to receive Hidac (P = 0.001), a trend for higher mortality in remission induction (P = 0.062) and a decreased LFS (P < 0.0001). However, it was not associated with outcomes for patients receiving Hidac. In conclusion, survival for patients who received Hidac consolidation is satisfactory; however, socioeconomic factors may have selected patients to receive intensive Hidac consolidation.