HMT x PTP1B

Most (40-50%) acute myelogenous leukemias (AMLs) are cytogenetically normal (CN-AML).Many are of intermediate risk, and the prognosis may be partially based on their gene mutational profiles.A recent study has proposed genomic classification of AML based on driver mutations such as NPM1, TP53 and CEBPA, and how these distinct mol. subgroups may provide informed clin. implication.Sequencing of 63 patients (Supplementary Table S1) with whole exome or targeted exome (Supplementary Tables S2-S5, Supplementary Figures S1-S3) cumulatively identified 19 genes frequently (≥5%) mutated at diagnosis: NPM1 (27%), DNMT3A (24%), TET2 (17%), IDH2 (14%),CEBPA (13%), FLT3 (11%), KTM2C (10%), NRAS (10%), PTPN11 (10%), USH2A (8%), EZH2 (6%), IDH1 (6%), WT1 (6%),DYSF (5%), EGFR (5%), RELN (5%), RUNX1 (5%), TG (5%) and ZFHX4 (5%) (Supplementary Figure S4, Supplementary Tables S6 and S7).When patients were divided based on their French-American-Britsh classification, DNMT3A and NPM1 mutations were more prevalent in M4 AML compared with either M2 or M1 (P<0.05; Supplementary Figure S5).Patients ≥60 years had significantly more frequent mutations of TET2 (30%) vs those <60 years of age (6%), and those ≥60 years had less frequent CEBPA mutations compared with those age <60 years (3% vs 21%, resp.; Figure 1a, Supplementary Table S8).Moreover, the frequencies of RUNX1,TET2 and FLT3 mutations were significantly different between our cohort and all TCGA AMLs: 17% vs 8% for TET2, 11% vs 28% for FLT3 and 5% vs 16% for RUNX1, resp. (Supplementary Table S9).Frequency difference was also noted in less common or novel mutations such as USH2A, DYSF and RELN (Supplementary Table S10).These observations indicate that FLT3-ITD^negMLL-PTD^neg CN-AML is a different population from other AMLs.Several novel mutations (for example, USH2A, FBLN2, RELN and PTPN1; Supplementary Table S10) have not been previously associated with AML, examination of their functions may elucidate their relevance in the disease progression of FLT3-ITD^negMLL-PTD^neg CN-AML.Our results suggest CN-AML without either FLT3-ITD or MLL-PTD is a highly heterogeneous disease driven by different drivers and may not be treated as a single cohort for risk stratification.Of clin. relevance, >15% of individuals in morphol. complete remission still retained a detectable preleukemic clone of either DNMT3A, TET2 or IDH1/2 by genomic sequencing.Those patients harboring persistent mutation at remission may require close monitoring for detection of driver mutations associated with frank leukemia (for example, NPM1, RUNX1, WT1 and so on).This may enable physicians to capture the early signs of possible relapse and institute aggressive therapy (for example, allotransplant).

Diabetic nephropathy (DN) is the primary microvascular complication of diabetes mellitus and may result in end-stage renal disease. The overproduction of various inflammatory factors is involved in the pathogenesis of DN. Protein tyrosine phosphatase 1B (PTP1B) modulates the expression of a series of cytokines and nuclear factor kappa B (NF-κB) activity. cAMP response element-binding protein (CREB) and lysine methyltransferase 5A (KMT5A) have been reported to participate in the maintenance of a healthy endothelium. In the present study, we hypothesise that CREB associates with KMT5A to modulate PTP1B expression, thus contributing to high glucose-mediated glomerular endothelial inflammation. Our analyses revealed that plasma inflammatory factor levels, glomerular endothelial p65 phosphorylation and PTP1B expression were increased in DN patients and rats. In vitro, high glucose increased endothelial inflammatory factor levels and p65 phosphorylation by augmenting PTP1B expression in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose decreased CREB and KMT5A expression. CREB overexpression and KMT5A overexpression both inhibited high glucose-induced PTP1B expression, p65 phosphorylation and endothelial inflammatory factor levels. si-CREB- and sh-KMT5A-induced p65 phosphorylation and endothelial inflammatory factor levels were reversed by si-PTP1B. Furthermore, CREB was associated with KMT5A. Mechanistic research indicated that CREB and histone H4 lysine 20 methylation (H4K20me1, a downstream target of KMT5A) occupy the PTP1B promoter region. sh-KMT5A augmented PTP1B promoter activity and activated the positive effect of si-CREB on PTP1B promoter activity. Our in vivo study demonstrated that CREB and KMT5A were downregulated in glomerular endothelial cells of DN patients and rats. In conclusion, CREB associates with KMT5A to promote PTP1B expression in vascular endothelial cells, thus contributing to hyperglycemia-induced inflammatory factor levels in DN patients and rats.