Co-operative leukemogenesis in acute myeloid leukemia and acute promyelocytic leukemia reveals C/EBP  as a common target of TRIB1 and PML/RARA

Abstract

T he 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.Co-operative leukemogenesis in acute myeloid leukemia and acute promyelocytic leukemia reveals C/EBPα as a common target of TRIB1 and PML/RARA

TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence

“…High TRIB3 expression enhanced the resistance of APL cells to anti-APL therapy. This is similar to the recent observation that elevated TRIB1 expression confers ATRA resistance in APL (Keeshan et al, 2016). Interestingly, ATRA/As 2 O 3 therapy induced TRIB3 expression, which may compromise the therapeutic effects of ATRA/As 2 O 3 .…”

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

“…As described, the TRIB1 gene is located on chromosome 8, the most common chromosomal gain in human AML and APL (distinguished by the fusion oncogene PML/RARA). The hypothesis that TRIB1 and PML/RARA cooperate has been tested and, while they do not cooperate to drive a shorter latency leukemia in vivo , TRIB1 and PML/RARA have functionally redundant inhibitory effects on C/EBPα, which also impacts responses [72] to therapeutic All- Trans Retinoic Acid (ATRA, Figure 5). …”

Inverse and correlative relationships between TRIBBLES genes indicate non-redundant functions during normal and malignant hemopoiesis

“…There is an interesting clustering of PPARa transcription factor with a positive correlation with TRIB2 and a negative correlation with TRIB1 and TRIB3 in normal cells. Overexpression data has shown overlapping roles for TRIB1 and TRIB2 in AML(12,52,53). Therefore, the nonredundancy of TRIB1 and TRIB2 in normal and malignant haemopoiesis is a necessary future line of functional investigation.…”