Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells

Cai, Zhigang; Aguilera, Fabiola; Ramdas, Baskar; Daulatabad, Swapna Vidhur; Srivastava, Rajneesh; Kotzin, Jonathan J.; Carroll, Martin; Wertheim, Gerald; Williams, Adam; Janga, Sarath Chandra; Zhang, Chi; Henao‐Mejia, Jorge; Kapur, Reuben

doi:10.1016/j.celrep.2020.107816

Cited by 25 publications

(24 citation statements)

References 26 publications

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“…Interestingly, in addition to the usual suspects, noted above, RNA-seq analysis revealed a significant upregulation in the expression of an anti-apototic lncRNA, Morrbid in Tet2 +/-;Ins2 Akita/+ compound mutant mice ( Figure 2D), which was verified by qRT-PCR analysis ( Figure 2B). We have recently demonstrated increased expression of MORRBID in human AML cells, which is associated with poor patient survival (11). Given the presence of elevated IL-6 and increased Morrbid expression in Tet2 +/-;Ins2 Akita/+ compound mutants, combined with the manifestation of a hyper-inflammatory condition, we hypothesized that inflammation-induced Morrbid expression significantly contributes to the mortality and the manifestation of the severe MPN/AML phenotype driven via the cooperative interaction between Tet2 +/and Ins2 Akita/+ in Tet2 +/-;Ins2 Akita/+ mice.…”

Section: Resultsmentioning

confidence: 99%

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

Cai¹,

Lu²,

Zhang³

et al. 2021

Journal of Clinical Investigation

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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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Section: Resultsmentioning

confidence: 99%

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

Cai¹,

Lu²,

Zhang³

et al. 2021

Journal of Clinical Investigation

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“…This interaction is further regulated by lncRNAs. LncRNA MORBID was found to be overexpressed in AML and downregulates the expression of BIM, which resulted in increased growth of the AML cells (Cai et al, 2020). The ZEB2‐AS1 was reported to be overexpressed in myeloid leukemia (X. Shi, Li, Ma, et al, 2019).…”

Section: Role Of Lncrnas In Cell Proliferation Survival and Different...mentioning

confidence: 99%

“…To date, a variety of lncRNAs were found to be correlated with the diagnosis and prognosis of AML. Overexpression of MORRBID was found to be correlated with poor prognosis in AML (Cai et al, 2020). The lower levels of the IRAIN lncRNA showed a correlation with high‐risk, bad prognosis, worse overall survival, as well as disease‐free survival along with elevated counts of blasts and WBCs (Pashaiefar et al, 2018).…”

Section: Lncrnas As Reliable Prognostic and Diagnostic Factorsmentioning

confidence: 99%

Long noncoding RNAs: A novel insight in the leukemogenesis and drug resistance in acute myeloid leukemia

Kirtonia

Ashrafizadeh

Zarrabi

et al. 2021

Journal Cellular Physiology

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Acute myeloid leukemia (AML) is a common hematological disorder with heterogeneous nature that resulted from blocked myeloid differentiation and an enhanced number of immature myeloid progenitors. During several decades, different factors, including cytogenetic, genetic, and epigenetic have been reported to contribute to the pathogenesis of AML by inhibiting the differentiation and ensuring the proliferation of myeloid blast cells. Recently, long noncoding RNAs (lncRNAs) have been considered as potential diagnostic, therapeutic, and prognostic factors in different human malignancies including AML. Altered expression of lncRNAs is correlated with the transformation of hematopoietic stem and progenitor cells into leukemic blast cells because of their distinct role in the key cellular processes. We discuss the significant role of lncRNAs in the proliferation, survival, differentiation, leukemic stem cells in AML and their involvement in different molecular pathways (insulin-like growth factor type I receptor, FLT3, c-KIT, Wnt, phosphatidylinositol 3-kinase/ protein kinase-B, microRNAs), and associated mechanisms such as autophagy, apoptosis, and glucose metabolism. In addition, we aim to highlight the role of lncRNAs as reliable biomarkers for diagnosis, prognosis, and drug resistance for precision medicine in AML.

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“…As Morrbid is a prosurvival, long noncoding RNA that selectively suppresses BIM transcription, TET2 loss‐induced enhanced expression of Morrbid led to reduced apoptosis and promoted survival of Tet2 −/− HSPCs under basal conditions as well as inflammation (Figure 4). 48 Of note, MORRBID is overexpressed in murine Tet2 −/− Flt3 ITD AML and a subset of human AML with TET2 mutation 49 . These results together suggest that Tet2 loss confers HSPCs with survival advantage during inflammation in an IL‐6‐dependent manner.…”

Section: Roles Of Inflammatory Signals In Clonal Expansion Of Tet2‐dementioning

confidence: 87%

TET2: A cornerstone in normal and malignant hematopoiesis

Kunimoto

Nakajima

2020

Cancer Science

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Epigenetic modifiers that regulate DNA cytosine methylation and histone methylation/acetylation are recurrent targets of genetic aberrations in hematological malignancies. 1 Ten-eleven translocation 2 (TET2) is one of the TET family proteins that either catalyzes serial oxidation of 5-methylcytosine (5mC) or mediates histone modifications. 2-6 Genomic studies have uncovered recurrent TET2 loss-of-function mutations in various hematological malignancies as well as in clonal hematopoiesis of indeterminate potential (CHIP), 7-17 suggesting a critical role for TET2 in both normal and malignant hematopoiesis. In this review, we will summarize the most recent updates regarding TET2 biology, focusing on its key roles in hematopoietic stem cell (HSC) self-renewal/differentiation, inflammatory response, and leukemogenesis.

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Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells

Cited by 25 publications

References 26 publications

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

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

Long noncoding RNAs: A novel insight in the leukemogenesis and drug resistance in acute myeloid leukemia

TET2: A cornerstone in normal and malignant hematopoiesis

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