DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.

Increasing evidence links metabolism, protein synthesis, and growth signaling to impairments in the function of hematopoietic stem and progenitor cells (HSPC) during aging. The Lin28b/Hmga2 pathway controls tissue development and the postnatal downregulation of this pathway limits the self-renewal of adult vs. fetal hematopoietic stem cells (HSC). Igf2bp2 is an RNA binding protein downstream of Lin28b/Hmga2, which regulates mRNA stability and translation. The role of Igf2bp2 in HSC aging is unknown. Here, we show in an analysis of wildtype and Igf2bp2 knockout mice that Igf2bp2 regulates oxidative metabolism in HSPC and the expression of metabolism, protein synthesis, and stemness-related genes in HSC of young mice. Interestingly, Igf2bp2 expression and function strongly decline in HSC aging. In young mice, Igf2bp2-deletion mimics aging-related changes of HSC, including changes in Igf2bp2-target gene expression and the impairment in colony formation and repopulation capacity. In aged mice, Igf2bp2 gene status has no effect on these parameters in HSC. Unexpectedly, Igf2bp2 deficient mice exhibit an amelioration of the aging-associated increase of HSC numbers and myeloid skewed differentiation. Together, Igf2bp2 controls mitochondrial metabolism, protein synthesis, growth, and stemness of young HSC, which is required for full HSC function at young adult age. However, Igf2bp2 gene function is lost during aging and it appears to contribute to HSC aging in two ways: (i) the aging-related loss of Igf2bp2 gene function impairs the growth and repopulation capacity of aging HSC and (ii) the activity of Igf2bp2 at young age contributes to aging-associated HSC expansion and myeloid skewing.

Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed a similar frequency in cases and controls. EGFR-AS1 expressed significantly high level in tumors and EGFR-A isoform expression showed significant positive correlation (r = 0.6464, p < 0.0001) with reference to EGFR-AS1 expression levels, consistent with larger TCGA HNSCC tumor dataset. Our bioinformatic analysis showed enrichment of alternative splicing marks H3K36me3 and presence of intronic polyA sites spanning around exon 15a and 15b of EGFR facilitates skipping of exon 15b, thereby promoting the splicing of EGFR-A isoform. In addition, high level expression of PTBP1 and its binding site in EGFR and EGFR-AS1 enhances the expression of EGFR-A isoform (r = 0.7404, p < 0.0001) suggesting that EGFR-AS1 expression modulates the EGFR-A and D isoforms through alternative splicing. In addition, this polymorphism creates a binding site for miR-891b in EGFR-AS1 and may negatively regulate the EGFR-A. Collectively, our results suggested the presence of genetic variant in EGFR-AS1 modulates the expression of EGFR-D and A isoforms.

Background: Deletion of the long arm of chromosome 9, del(9q), is a recurrent genomic abnormality, which occurs at a frequency of ~2% in AML. Interestingly, deletions of 9q are mainly found in t(8;21)-positive AML, as well as in AML with NPM1 (NPM1mut) or CEBPA (CEBPAmut) gene mutation, thereby suggesting that del(9q) can act as cooperating event in these prognostically favorable AML subgroups. Aims: In order to dissect the biology of AML with del(9q), we comprehensively characterized a large cohort of 9q21 deleted cases (n=45) at the molecular level. Methods: We performed SNP 6.0 microarray analysis to delineate the minimally deleted region on 9q, and we analyzed gene expression in selected cases to determine whether 9q21 deletions are displaying a characteristic expression pattern. Potential candidate genes were further studied by shRNA based knock-down experiments in cell line models. Finally, we performed whole exome sequencing (WES) of paired diagnostic and remission samples from n=20 del(9q) patients with NPM1mut (n=7), NPM1wt/CEBPAmut (n=7), and t(8;21) (n=6) to identify additional aberrations cooperating with 9q loss in leukemogenesis. Results: By SNP microarray analysis, we could confirm a minimally deleted region (MDR) on 9q21 encompassing seven genes (GKAP1, KIF27, C9orf64, HNRNPK, RMI1, SLC28A3, NTRK2). By targeted resequencing in n=50 non-9q deleted cases, we detected a mutation in HNRNPK, which was recently confirmed to be recurrently mutated by The Cancer Genome Atlas (TCGA) project. These findings point to HNRNPK as the most important candidate gene of the MDR. HNRNPK encodes for a ubiquitously expressed heterogeneous nuclear ribonucleoprotein (hnRNP), which influences pre-mRNA processing and other aspects of mRNA metabolism, and it is thought to play a role during cell cycle progression. To further evaluate the biology underlying 9q deleted/HNRNPK haploinsufficient cases, gene expression data were generated by microarray technology comparing NPM1mut cases with and without del(9q) (n=11 vs n=119, respectively). These analyses showed deregulated expression of genes involved in splicing and mRNA processing, and there was an overlap with gene expression changes following shRNA-mediated HNRNPK knock-down in AML cell lines, which also suggested a growth advantage for haploinsufficient cells. While these data further support that HNRNPK might play a cooperating role in AML, we were eager to see whether there are additional mutations commonly linked to del(9q). By WES, we detected on average 7.8 somatic protein altering point mutations per sample (missense and nonsense SNVs) and 2.5 frameshift insertions or deletions affecting genes known to play a role in AML as well as genes not yet linked to AML. In accordance with the general mutational spectrum of t(8;21), NPM1 or CEBPA mutant AML, we identified mutations in known epigenetic regulators such as ASXL1, ASXL2, TET2 or DNMT3A, but we also could find novel somatic mutations in additional genes involved in the regulation of the chromatin structure such as BRD3 or BRWD3. Furthermore, we identified mutations in genes associated with mRNA processing and RNA splicing,as well as mutations affecting the RAS- signaling pathway and DNA repair mechanisms. Conclusions: While ongoing analyses are likely to identify additional gene mutations in del(9q) AML, first results suggest HNRNPK haploinsufficiency as a potential "driver" mutation playing a role in the pathomechanism of 9q deleted AML. A better understanding of the HNRNPK function in normal hematopoietic cells as well as leukemia cells without del(9q), and studying the impact of HNRNPK mutations in AML might enable novel therapeutic approaches for del(9q)/HNRNPKmut AML. These authors contributed equally to the work: AD and SRC as well as KD and LB. Supported by: FP7 NGS-PTL project, and DFG SFB 1074 B3 project. Disclosures No relevant conflicts of interest to declare.