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.
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