title: Co-operative leukemogenesis in acute myeloid leukemia and acute promyelocytic leukemia reveals C/EBPα as a common target of TRIB1 and PML/RARA.
abstract: The PML/RARA fusion protein occurs as a result of the t(15;17) translocation in the acute promyelocytic leukemia subtype of human acute myeloid leukemia. Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia, including acute promyelocytic leukemia. 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 leukemogenesis 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 co-operated in leukemogenesis for wild-type bone marrow, TRIB1 provided no selective advantage to cells expressing PML/RARA. We hypothesized that this lack of co-operation 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 leukemia 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 leukemia, and highlighting the key role of C/EBPs in acute promyelocytic leukemia pathogenesis and therapeutic response. In addition, the co-operativity we observed between MYC and TRIB1 in the absence of PML/RARA show that, outside of acute promyelocytic leukemia, gain of both genes may drive selection for trisomy 8.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, UK scott.kogan@ucsf.edu karen.keeshan@glasgow.ac.uk.
authors.forename: Karen
authors.initials: K
authors.lastname: Keeshan
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Vieugué
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
authors.forename: Shahzya
authors.initials: S
authors.lastname: Chaudhury
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
authors.forename: Loveena
authors.initials: L
authors.lastname: Rishi
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, USA.
authors.forename: Coline
authors.initials: C
authors.lastname: Gaillard
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, UK.
authors.forename: Nader
authors.initials: N
authors.lastname: Omidvar
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, USA scott.kogan@ucsf.edu karen.keeshan@glasgow.ac.uk.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002898:Chromosomes, Human, Pair 8; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000473:pathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D014314:Trisomy
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D016271:Proto-Oncogene Proteins c-myc; C493170:TRIB1 protein, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D017346:Protein Serine-Threonine Kinases