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

被引：27

作者：

Cai, Zhigang ^{[1
,2
]}

Aguilera, Fabiola ^{[1
]}

Ramdas, Baskar ^{[1
]}

Daulatabad, Swapna Vidhur ^{[3
]}

Srivastava, Rajneesh ^{[3
]}

Kotzin, Jonathan J. ^{[4
]}

Carroll, Martin ^{[4
]}

Wertheim, Gerald ^{[4
]}

Williams, Adam ^{[5
]}

Janga, Sarath Chandra ^{[3
]}

Zhang, Chi ^{[6
]}

Henao-Mejia, Jorge ^{[4
,7
,8
]}

Kapur, Reuben ^{[1
,2
]}

机构：

[1] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA

[3] Indiana Univ Purdue Univ, Sch Informat & Comp, Indianapolis, IN 46202 USA

[4] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA

[5] Jackson Lab Genom Med, Farmington, CT USA

[6] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[7] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA

[8] Childrens Hosp Philadelphia, Div Protect Immun, Philadelphia, PA 19104 USA

来源：

CELL REPORTS | 2020年 / 31卷 / 12期

基金：

美国国家卫生研究院;

关键词：

HEMATOPOIETIC STEM-CELL; TET2; CANCER; LEADS; FLT3;

D O I：

10.1016/j.celrep.2020.107816

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 FLT3(ITD). Mice with individual mutations of Tet2 or Flt3(ITD) 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.

引用

页数：15

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