Browsing by Author "Wertheim, Gerald"

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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.