Browsing by Subject "TET2"

Now showing 1 - 4 of 4
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    Driver Mutations in Leukemia Promote Disease Pathogenesis through a Combination of Cell-Autonomous and Niche Modulation
    (Elsevier, 2020-07-14) Ramdas, Baskar; Mali, Raghuveer Singh; Palam, Lakshmi Reddy; Pandey, Ruchi; Cai, Zhigang; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Kapur, Reuben; Pediatrics, School of Medicine
    Studies of patients with acute myeloid leukemia (AML) have led to the identification of mutations that affect different cellular pathways. Some of these have been classified as preleukemic, and a stepwise evolution program whereby cells acquire additional mutations has been proposed in the development of AML. How the timing of acquisition of these mutations and their impact on transformation and the bone marrow (BM) microenvironment occurs has only recently begun to be investigated. We show that constitutive and early loss of the epigenetic regulator, TET2, when combined with constitutive activation of FLT3, results in transformation of chronic myelomonocytic leukemia-like or myeloproliferative neoplasm-like phenotype to AML, which is more pronounced in double-mutant mice relative to mice carrying mutations in single genes. Furthermore, we show that in preleukemic and leukemic mice there are alterations in the BM niche and secreted cytokines, which creates a permissive environment for the growth of mutation-bearing cells relative to normal cells.
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    Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells
    (Elsevier, 2020-06-23) 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; Pediatrics, School of Medicine
    Inhibition of anti-apoptotic proteins BCL-2 and MCL-1 to release pro-apoptotic protein BIM and reactivate cell death could potentially be an efficient strategy for the treatment of leukemia. Here, we show that a lncRNA, MORRBID, a selective transcriptional repressor of BIM, is overexpressed in human acute myeloid leukemia (AML), which is associated with poor overall survival. In both human and animal models, MORRBID hyperactivation correlates with two recurrent AML drivers, TET2 and FLT3ITD. Mice with individual mutations of Tet2 or Flt3ITD develop features of chronic myelomonocytic leukemia (CMML) and myeloproliferative neoplasm (MPN), respectively, and combined presence results in AML. We observe increased levels of Morrbid in murine models of CMML, MPN, and AML. Functionally, loss of Morrbid in these models induces increased expression of Bim and cell death in immature and mature myeloid cells, which results in reduced infiltration of leukemic cells in tissues and prolongs the survival of AML mice.
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    Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
    (SpringerNature, 2017-04-25) Pan, Feng; Wingo, Thomas S.; Zhao, Zhigang; Gao, Rui; Makishima, Hideki; Qu, Guangbo; lin, Li; Yu, Miao; Ortega, Janice R.; Wang, Jiapeng; Nazha, Aziz; Chen, Li; Yao, Bing; Liu, Can; Chen, Shi; Weeks, Ophelia; Ni, Hongyu; Phillips, Brittany Lynn; Huang, Suming; Wang, Jianlong; He, Chuan; Li, Guo-Min; Radivoyevitch, Tomas; Aifantis, Iannis; Maciejewski, Jaroslaw P.; Yang, Feng-Chun; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, School of Medicine
    TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2-/- tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2-/- Lin-c-Kit+ cells shows higher mutation frequencies in Tet2-/- cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.
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    The Role of Inflammatory Signaling Pathways in TET2-Deficient Hematological Malignancies
    (2024-08) Burns, Sarah Sterling; Kapur, Reuben; Davé, Utpal; Ware, Stephanie; Herbert, Brittney-Shea
    Loss of the TET2 gene, which is commonly mutated in the pre-leukemic condition clonal hematopoiesis of indeterminate potential (CHIP) and hematological malignancies, dysregulates inflammation, including the interleukin-1 (IL-1) and interleukin-6 (IL-6) pathways. As TET2 mutations are often present in hematopoietic stem and progenitor cells, dysregulation of these pathways may contribute to leukemogenesis and may catalyze the progression of pre-leukemic states, such as CHIP, to malignancy. Tet2-/- mice exhibit splenomegaly, myeloid expansion, and myeloid malignancy. To investigate the effects of inactivation of IL-1 receptor, type 1 (Il-1r1) and Il-6 on Tet2-deficient mature and immature hematopoietic cells, Tet2-/-;Il-1r1-/- and Tet2-/-;Il-6-/- mice were generated. Interestingly, Il-1r1 loss rescued the leukemic phenotypes associated with Tet2 inactivation, including expansion of myeloid cells, suppression of lymphoid cells, and restoration of spleen size. These phenotypes were recapitulated with competitive transplant, suggesting that IL-1R1 exerts a cell autonomous role. Mice transplanted with Tet2-/-;Il-1r-/- bone marrow cells exhibited differential regulation of specific myeloid and lymphoid subpopulations. At the stem-cell level, the frequencies of early myeloid Lin-;c- Kit+, early lymphoid Lin-;Sca1+ progenitors, and multipotent progenitor populations 2 and 3/4 were corrected, and a pronounced and reciprocal switch in the levels of Lin-;c- Kit+ and Lin-;Sca1+ cells was detected. Aged Tet2-/-;Il-1r-/- mice retained some of these phenotypes. Acute myeloid leukemia with higher IL-1R1 expression had reduced survival, indicating potential clinical implications. Similar to Tet2-/-;Il-1r1-/- mice, Tet2-/- ;Il-6-/- mice showed correction of myeloid cell expansion and lymphocyte suppression; however, they also demonstrated a significant increase in long-term hematopoietic stem cells and possible splenic extramedullary hematopoiesis, highlighting unique roles of IL- 6 in the pre-leukemic context. Collectively, these findings suggest that IL-1R1- and IL-6- dependent signaling exhibit overlapping functions but also have distinct roles in leukemogenesis that may have important implications for the clinical management of CHIP and hematological malignancies.