Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid
Zhigang Cai, Xiaoyu Lu, Chi Zhang, Sai Nelanuthala, Fabiola Aguilera, Abigail Hadley, Baskar Ramdas, Fang Fang, Kenneth Nephew, Jonathan J. Kotzin, Adam Williams, Jorge Henao-Mejia, Laura Haneline, Reuben Kapur
Zhigang Cai, Xiaoyu Lu, Chi Zhang, Sai Nelanuthala, Fabiola Aguilera, Abigail Hadley, Baskar Ramdas, Fang Fang, Kenneth Nephew, Jonathan J. Kotzin, Adam Williams, Jorge Henao-Mejia, Laura Haneline, Reuben Kapur
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Concise Communication Hematology Inflammation

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.

Authors

Zhigang Cai, Xiaoyu Lu, Chi Zhang, Sai Nelanuthala, Fabiola Aguilera, Abigail Hadley, Baskar Ramdas, Fang Fang, Kenneth Nephew, Jonathan J. Kotzin, Adam Williams, Jorge Henao-Mejia, Laura Haneline, Reuben Kapur

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Figure 1

An age-dependent MPN/AML model driven by HG stress and preleukemic mutation.

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An age-dependent MPN/AML model driven by HG stress and preleukemic mutat...
(A) Schematic for the generation of compound mutant Tet2+/– Ins2Akita/+ mice along with WT, Tet2+/–, and Ins2Akita/+ controls. (B) Kaplan-Meier survival curve for the compound mutant Tet2+/– Ins2Akita/+ mice and controls. Only compound mutant Tet2+/– Ins2Akita/+ mice showed early mortality, between 6 and 9 months of age, with 100% penetration. The median survival for the compound mutant mice was approximately 7 months (221 days), whereas all control mice survived beyond 300 days, after which the experiment was discontinued. (C) At the end stage of life (6–9 months of age), all the compound mutant Tet2+/– Ins2Akita/+ mice displayed a visible myeloid sarcoma under the skin around the ocular area on 1 or both sides (red arrow), as well as pale bones (blue arrow) and splenomegaly. (D) Spleen weights at 6–9 months of age, when the compound mutant mice became moribund. (E) Mutant Ins2Akita/+ and Tet2+/– Ins2Akita/+ mice manifested an increase in blood glucose levels and a decrease in body weight compared with WT and Tet2+/– mice throughout all stages. The plots show data for the mice at 5 months of age. (F) Hematologic analysis of PB using the automatic blood cell counter Element HT5. NE, neutrophil. (G) Analysis of myeloid cell compartments by flow cytometry using staining with Ly6G and Mac1 antibodies. (H) Analysis of BM mononuclear cells by flow cytometry using antibodies that recognize cKit and Mac1. (I) Quantification of the frequency of HSPCs and mature cells in the BM. n = 4–10 mice. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (D–I). Data in B were analyzed with GraphPad Prism 6, using the Kaplan-Meier survival package. Freq., frequency.