Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid

Abstract

Diabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic stress (HG) in blood cancer is poorly understood. 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 TET2. TET2-mutant pre-LHSC/Ps require additional hits to evolve into a full-blown leukemia and/or aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, extrinsic factors are poorly understood. Utilizing a mouse model bearing haploinsufficiency of Tet2, to mimic the human pre-LHSC/P condition and HG stress, in the form of an Ins2 Akita/+ mutation, which induces HG, 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. Morrbid loss in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent AML/MPN and suggest that HG acts as an environmental driver for myeloid neoplasm, which could be prevented by reducing the expression of inflammation-related lncRNA Morrbid.

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;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 senescenceassociated secretory phenotype (SASP) (Franceschi et al, 2018;Santoro et al, 2020).…”

Clonal hematopoiesis and its emerging effects on cellular therapies

“…By using more sensitive assays it was observed that in samples with low allele frequency (<0.02 VAF) the mutational burden was equally distributed between different lineages [21]. As the mutational spectrum differs between high and low mutational burden samples, myeloid skewing probably does not represent a phenomenon of CH in general, instead it could reflect a feature of clones acquiring dominance at later time points, potentially due to proinflammatory cytokine loops [44,49]. Despite myeloid skewing and risk of transformation to myeloid neoplasms (MDS/AML; low in absolute numbers) being common, CHIP should not be regarded as a disorder restricted to the myeloid lineage but has pleiotropic consequences.…”

Inflammatory signals from fatty bone marrow supports the early stages of DNMT3a driven clonal hematopoiesis

“…These findings might have clinical relevance as anti IL-6 treatments are available and can be used to control DNMT3A driven CH. Chronic kidney disease (CKD) (54) and hyperglycemia (41) are characterized by increased IL-6 levels and increased FBM (46). Adverse outcomes of CKD correlate with IL-6 levels (55).…”

“…In this regard it seems like different inflammatory states can promote the fitness of preL-HSPCs. It seems that the effects of different pathological states on pLMs coalesce to inflammation: hyperglycemia (41), heart disease(51), ulcerative colitis (52), HIV (40), mycobacterium chronic infection (42) and exposure to microbiome (50). CH, in turn, promotes other pathological states by a vicious cycle of enhanced inflammation (53).…”