Hyperglycemia Cooperates with Tet2 Heterozygosity to Induce Leukemia Driven By Pro-Inflammatory Cytokine Induced Lncrna Morrbid

Abstract

Diabetes mellitus (DM) is a risk factor for cancer development. However, the role of DM induced hyperglycemic stress (HG) in the development of blood cancer is poorly understood, largely due to lack of appropriate animal models. Epidemiologic studies show that individuals with DM are more likely to possess higher rate of mutations in genes found in pre-leukemic stem and progenitor cells (pre-LHSC/Ps) including in the epigenetic regulator TET2. TET2-mutant pre-LHSC/Ps require additional hits to evolve into a full-blown leukemia and/or aggressive myeloproliferative neoplasm (MPN). Cell intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the role of extrinsic factors is poorly understood. Utilizing a novel mouse model bearing haploinsufficiency of Tet2, to mimic the human pre-LHSC/P condition and HG stress, in the form of an Ins2Akita/+mutation, which induces HG and Type-1 DM, we show that the compound mutant mice develop a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-seq revealed that this is in part due to upregulation of pro-inflammatory pathways, thereby generating a feed-forward loop, including the expression of an anti-apoptotic lncRNA Morrbid. Loss of Morrbid in the compound mutants rescues the lethality and mitigates the development of MPN/AML. Our results describe a novel mouse model for age-dependent AML/MPN and suggest that HG stress acts as an environmental driver for myeloid neoplasm, which could be effectively prevented by reducing the expression of inflammation-related lncRNA Morrbid. Disclosures No relevant conflicts of interest to declare.

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

“…Hyperglycaemia, the main pathological hallmark of diabetes mellitus, is associated with a range of disorders (Nolan et al, 2011). Recent studies have shown that hyperglycaemia leads to a pre‐aging and pro‐inflammatory state, termed inflamm‐aging, which increases the susceptibility to periodontal disease (Ferrucci & Fabbri, 2018; Fernandes et al, 2019; P. Zhang, Wang, et al, 2019; Cai et al, 2020). Inflamm‐aging refers to a chronic, low‐degree inflammatory phenotype associated with the ageing process, originating from two major contributors: cellular senescence and the senescence‐associated secretory phenotype (SASP) (Franceschi et al, 2018; Santoro et al, 2020).…”