Co-operative leukaemogenesis in acute myeloid leukaemia and acute promyelocytic leukaemia reveal C/EBPα as a common target of TRIB1 and PML/RARA

Keeshan, K. , Vieugué, P., Chaudhury, S. , Rishi, L., Gaillard, C., LIang, L., Garcia, E., Nakumura, T., Omidvar, N. and Kogan, S. C. (2016) Co-operative leukaemogenesis in acute myeloid leukaemia and acute promyelocytic leukaemia reveal C/EBPα as a common target of TRIB1 and PML/RARA. Haematologica, 101(10), pp. 1228-1236. (doi:10.3324/haematol.2015.138503) (PMID:27390356) (PMCID:PMC5046652)

[img]
Preview
Text
120280.pdf - Published Version

3MB

Abstract

The PML/RARA fusion protein occurs as a result of the t(15;17) translocation in the acute promyelocytic leukaemia subtype of human acute myeloid leukaemia. Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukaemia, including acute promyelocytic leukaemia. We previously demonstrated that gain of chromosome 8-containing MYC is of central importance in trisomy 8, but the role of the nearby TRIB1 gene has not been experimentally addressed in this context. We have now tested the hypothesis that both MYC and TRIB1 have functional roles underlying leukaemogenesis of trisomy 8 by using retroviral vectors to express MYC and TRIB1 in wild-type bone marrow and in marrow that expressed a PML/RARA transgene. Interestingly, although MYC and TRIB1 readily cooperated in leukaemogenesis for wild-type bone marrow, TRIB1 provided no selective advantage to cells expressing PML/RARA. We hypothesized that this lack of cooperation between PML/RARA and TRIB1 reflected a common pathway for their effect: both proteins targeting the myeloid transcription factor C/EBPα. In support of this idea, TRIB1 expression abrogated the All Trans-Retinoic Acid response of acute promyelocytic leukaemia cells in vitro and in vivo. Our data delineate the common and redundant inhibitory effects of TRIB1 and PML/RARA on C/EBPα providing a potential explanation for the lack of selection of TRIB1 in human acute promyelocytic leukaemia, and highlighting the key role of C/EBPs in acute promyelocytic leukaemia pathogenesis and therapeutic response. In addition, the cooperativity we observed between MYC and TRIB1 in the absence of PML/RARA show that, outside of acute promyelocytic leukaemia, gain of both genes may drive selection for trisomy 8.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen and Chaudhury, Dr Shahzya
Authors: Keeshan, K., Vieugué, P., Chaudhury, S., Rishi, L., Gaillard, C., LIang, L., Garcia, E., Nakumura, T., Omidvar, N., and Kogan, S. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Haematologica
Publisher:Ferrata Storti Foundation
ISSN:0390-6078
ISSN (Online):1592-8721
Published Online:06 July 2016
Copyright Holders:Copyright © 2016 Ferrata Storti Foundation
First Published:First published in Haematologica 101(10):1228-1236
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
623941Targeting Trib2 oncogenic signalling in normal and malignant stem cells.Karen KeeshanBloodwise (BLOODWIS)13011RI CANCER SCIENCES