Oncotarget

Research Papers:

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

Caitriona O'Connor, Krishna Yalla, Mara Salomé, Hothri Ananyambica Moka, Eduardo Gómez Castañeda, Patrick A. Eyers and Karen Keeshan _

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Oncotarget. 2018; 9:14977-14992. https://doi.org/10.18632/oncotarget.24525

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Abstract

Caitriona O’Connor1, Krishna Yalla1, Mara Salomé1, Hothri Ananyambica Moka1, Eduardo Gómez Castañeda1, Patrick A. Eyers2 and Karen Keeshan1

1Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 0XB, UK

2Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK

Correspondence to:

Karen Keeshan, email: Karen.Keeshan@glasgow.ac.uk

Keywords: Trib2; AML; chemotherapy; BCL2

Received: October 11, 2017    Accepted: February 10, 2018    Epub: February 19, 2018    Published: March 13, 2018

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.


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