Subject(s)
COVID-19 , Leukemia, Myeloid, Acute , Adult , Brazil/epidemiology , Humans , SARS-CoV-2 , Surveys and QuestionnairesABSTRACT
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.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Leukemia, Promyelocytic, Acute/pathology , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Adult , Aged , Animals , Anthracyclines/pharmacology , Anthracyclines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease-Free Survival , Female , Gene Knockdown Techniques , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Leukocyte Count , Male , Membrane Microdomains/metabolism , Mice , Middle Aged , Retrospective Studies , Survival Analysis , Tretinoin/pharmacology , Tretinoin/therapeutic use , Xenograft Model Antitumor Assays , Young AdultABSTRACT
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.