{"doi":"10.1172/jci140707","title":"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 (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.","journal":"Journal of Clinical Investigation","year":2020,"id":63375,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":45,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":335022,"name":"Xiaoyu Lu","orcid":"0000-0003-3256-0312","position":1,"is_corresponding":false},{"id":334696,"name":"Chi Zhang","orcid":"0000-0001-9553-0925","position":2,"is_corresponding":false},{"id":335023,"name":"Sai Nelanuthala","orcid":"0000-0003-3517-0328","position":3,"is_corresponding":false},{"id":335024,"name":"Fabiola Aguilera","orcid":"0000-0001-9169-026X","position":4,"is_corresponding":false},{"id":335025,"name":"Abigail Hadley","orcid":"0000-0001-7359-5787","position":5,"is_corresponding":false},{"id":335026,"name":"Baskar Ramdas","orcid":"0009-0006-2206-5720","position":6,"is_corresponding":false},{"id":314338,"name":"Fang Fang","orcid":"0000-0002-7160-5723","position":7,"is_corresponding":false},{"id":314340,"name":"Kenneth P. Nephew","orcid":"0000-0003-2192-1346","position":8,"is_corresponding":false},{"id":335027,"name":"Jonathan J. Kotzin","orcid":"0000-0001-5179-2034","position":9,"is_corresponding":false},{"id":335028,"name":"Adam Williams","orcid":"0000-0002-5151-4103","position":10,"is_corresponding":false},{"id":305887,"name":"Jorge Henao‐Mejia","orcid":"0000-0003-2044-1105","position":11,"is_corresponding":false},{"id":332981,"name":"Laura S. Haneline","orcid":null,"position":12,"is_corresponding":false},{"id":335029,"name":"Reuben Kapur","orcid":"0000-0003-2225-1700","position":13,"is_corresponding":false},{"id":335021,"name":"Zhigang Cai","orcid":"0000-0001-7657-8843","position":0,"is_corresponding":true}],"reference_count":14,"raw_metadata":null,"created_at":"2026-07-18T21:11:00.632961Z","pmid":"33090974","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}