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



O'Connor, Caitriona ORCID: 0000-0002-7638-9804, Yalla, Krishna, Salomé, Mara ORCID: 0000-0003-3267-650X, Moka, Hothri Ananyambica ORCID: 0000-0001-9696-3941, Castañeda, Eduardo Gómez, Eyers, Patrick A ORCID: 0000-0002-9220-2966 and Keeshan, Karen ORCID: 0000-0001-7266-0890
(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.

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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 <i>in vivo</i>. 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 <i>Bcl2</i> expression. There is significant correlation of high <i>TRIB2</i> and <i>BCL2</i> 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: Article
Uncontrolled Keywords: AML, BCL2, Trib2, chemotherapy
Depositing User: Symplectic Admin
Date Deposited: 27 Mar 2018 14:01
Last Modified: 19 Jan 2023 06:37
DOI: 10.18632/oncotarget.24525
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3019529