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 2

The MPN/AML-like phenotype in compound mutants is largely driven by progressive inflammation and inflammatory cytokine–induced lncRNA Morrbid.

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The MPN/AML-like phenotype in compound mutants is largely driven by prog...
(A) Serological analysis of PB samples from various genotypes showed an increase in G-CSF and IL-6 in compound mutant mice. (B) qRT-PCR analysis was performed to detect the expression of Tet2 and Morrbid in lineage-negative cells from mice of various genotypes. (C) GSEA derived from RNA-Seq data set on lineage-negative BM cells from 4 groups of mice (6–8 month of age). Comparisons between Tet2+/– Ins2Akita/+ and WT revealed significant changes in the innate immune pathway, the IL-6–mediated signaling pathway, and the TLR4/NF-κB signaling pathway. In addition, the JAK/STAT pathway demonstrated a trend toward upregulation in Tet2+/– Ins2Akita/+ mice compared with WT. NES, normalized enrichment score. (D) Representative quantitative graphs of various innate immune response–related genes derived from the RNA-Seq data set, including the Bim-targeting lncRNA Morrbid (shown in the bottom right panel). (E) Schematic for the generation of triple-mutant Tet2+/– Ins2Akita/+ Morrbid–/– mice along with WT, Tet2+/– Ins2Akita/+, and Morrbid–/– controls. (F) Loss of Morrbid in compound mutants rescued the lethality associated with them compared with controls. A total of 9 mice were analyzed in the Tet2+/– Ins2Akita/+ Morrbid–/– cohort, and 10 mice in each of the other cohorts. (G) Comparison of hematological values between Tet2+/– Ins2Akita/+ Morrbid–/– and Tet2+/– Ins2Akita/+ mice. (H) Splenomegaly and an aberrant myeloid cell/B cell imbalance in compound heterozygous mutants was reversed in Tet2+/– Ins2Akita/+ Morrbid–/– mice. (I) Serum levels of G-CSF and IL-6. Mice in G–I were approximately 6–8 months old. n = 2–13 mice. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (A, B, D, and G–I). Data in F were analyzed with GraphPad Prism 6, using the Kaplan-Meier survival package.