Trib2 expression in granulocyte-monocyte progenitors drives a highly drug resistant acute myeloid leukaemia linked to elevated Bcl2

O'Connor, C., Yalla, K., Salome, M. , Moka, H. A., Gómez Castañeda, E., Eyers, P. A. and Keeshan, K. (2018) Trib2 expression in granulocyte-monocyte progenitors drives a highly drug resistant acute myeloid leukaemia linked to elevated Bcl2. Oncotarget, 9(19), pp. 14977-14992. (doi:10.18632/oncotarget.24525) (PMID:29599919) (PMCID:PMC5871090)

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Abstract

Trib2 pseudokinase has oncogenic and tumour suppressive functions depending on the cellular context. We investigated the ability of Trib2 to transform different haemopoietic stem and progenitor cells (HSPCs). Our study identified the granulocyte-macrophage progenitor (GMP) subpopulation as a potent leukaemia initiating cell of Trib2-driven AML in vivo. Trib2 transformed GMPs generated a fully penetrant and short latency AML. AML cells expressing elevated Trib2 led to a chemoresistant phenotype following chemotherapy treatment. We show that Trib2 overexpression results in an increase in BCL2 expression, and high Trib2 expressing cells are highly sensitive to cell killing by BCL2 inhibition (ABT199). Combined treatment with chemotherapeutic agents and BCL2 inhibition resulted in synergistic killing of Trib2+ AML cells. Trib2 transformed GMP AML cells showed more chemoresistance compared with HSPC derived Trib2 AML cells associated with higher Bcl2 expression. There is significant correlation of high TRIB2 and BCL2 expression in patient derived human AML cells. These data demonstrate that the cell of origin influences the leukaemic profile and chemotherapeutic response of Trib2+ AML. Combined TRIB2 and BCL2 expression in AML cells may have clinical utility relevant for monitoring drug resistance and disease relapse.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Moka, Miss Hothri Ananyamb and Keeshan, Dr Karen and Yalla, Dr Krishna and Gómez Castañeda, Eduardo and Salome, Ms Mara and O'Connor, Ms Caitriona
Authors: O'Connor, C., Yalla, K., Salome, M., Moka, H. A., Gómez Castañeda, E., Eyers, P. A., and Keeshan, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
ISSN (Online):1949-2553
Copyright Holders:Copyright © 2018 O’Connor et al.
First Published:First published in Oncotarget 9(19):14977-14992
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)18076RI CANCER SCIENCES
623941Targeting Trib2 oncogenic signalling in normal and malignant stem cells.Karen KeeshanBloodwise (LRF)13011RI CANCER SCIENCES
650661In-silico integration of primary CML stem cell polyomic datasets to identify kinase-independent networks and novel prognostic biomarkersHeather JorgensenBloodwise (BLOODWIS)13062ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C