Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T-ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targeting LDHA may be a potential strategy to improve T-ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene-targeting treatment on T-ALL and the underlying molecular mechanism. METHODS: Primary T-ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T-ALL cells. Quantitative real-time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluate ROS production after T-ALL cells were treated with oxamate. A T-ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene-editing technology, and then TUNEL, Western blotting, and T-ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T-ALL transgenic zebrafish. RESULTS: Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P < 0.001). Blocking LDHA significantly decreased the gene and protein expression of c-Myc, as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK-3ß) in the phosphatidylinositol 3'-kinase (PI3K) signaling pathway. LDHA gene knockdown delayed disease progression and down-regulated c-Myc mRNA and protein expression in T-ALL transgenic zebrafish. CONCLUSION: Targeting LDHA exerted an antileukemic effect on T-ALL, representing a potential strategy for T-ALL treatment.

The effect of the JAK2 inhibitor TG101209 against T cell acute lymphoblastic leukemia (T-ALL) is mediated by inhibition of JAK-STAT signaling and activation of the crosstalk between apoptosis and autophagy signaling.

Previous reports have shown that active JAK2 contributes to T cell acute lymphoblastic leukaemia (T-ALL) development and that JAK inhibitors may be a potential treatment for T-ALL. In the current study, the JAK2 inhibitor TG101209 was used to treat T-ALL cell lines and primary T-ALL cells. The effects of TG101209 on T-ALL cells were determined, and the signaling proteins related to cell growth, apoptosis and autophagy were analysed. The results indicated that TG101209 significantly inhibited T-ALL cell proliferation and induced cell apoptosis in a dose-dependent manner. The mechanisms involved the suppression of the JAK2-STAT signaling pathway and activation of apoptosis or autophagy. Additionally, a JAK2 gene copy gain (FISH) and up-regulated JAK2, LC3 and Beclin1 expression (western blotting) were observed in T-ALL samples compared with healthy controls, which implied that JAK2 is a target for T-ALL treatment. TG101209 initiated apoptosis and autophagy in T-ALL cells; therefore, this JAK2 inhibitor may be a potential drug or alternative therapy for T-ALL.

[Analysis of Clinical Characteristics in 31 Acute Myeloid Leukemia Patients with Chromosome 21 Aberrations].

OBJECTIVE: To investigate the clinical characteristics of 31 acute myeloid leukemia (AML) patients with chromosome 21 aberrations. METHODS: Karyotypes of 168 newly diagnosed AML patients in Second Xiangya Hospital from Jan 2014 to July 2016 were reviewed for the presence of chromosome 21 aberrations (accounting for 18.45%). Clinical manifestation, as well as prognostic gene mutations distribution and immune classification were analyzed. RESULTS: Out of 168 AML newly diagnosed patients, 31 cases with chromosome 21 aberrations including t(8;21) accounting for 67.74% (21/31), and trisomy 21 (16.13%,5/31), 2 variants were found as t(1; 21) and t(1; 21; 8); 77 cases had normal karyotype, and 60 cases possessed other chromosomes aberrations. Statistically significant differences did not exist among age, sex and white blood cell count (P>0.05). However, the 21 cases in chromosome aberrations group were predisposed to lower hemoglobin and platelet count(P<0.05). 5 cases of Trisomy 21 were characterized by M5 2 cases, M1 one case, M2 one case M4 one case. And the rate of C-kit/D816V mutation was higher in t(8;21) aberrations group when 7 prognostic genes including FLT3/ITD, C-kit/D816V, NPM1, DNMT3A, TET2 were analyzed, and the immune classification of t(8; 21) aberration group inclined to CD19+, CD34+ but CD33-, CD64-. And trisomy 21 displayed a trend to CD34+ and CD7+. CONCLUSION: Chromosome 21 is easily involved in acute myeloid leukemia. The patients with involvement of this aberration have characteristic clinic changes.