Skip to main content

Investigating Trib2-induced Acute Myeloid Leukaemia

Final Report Summary - TRIB2 IN AML (Investigating Trib2-induced Acute Myeloid Leukaemia)

In the past decade, the trend in overall incidence of acute myeloid leukaemia (AML) has generally been stable or slowly increasing in most European countries, and worldwide over 250 000 people are diagnosed with leukaemia each year, accounting for 2.5 % of all cancers. AML is a heterogenous disease that is caused by genetic and environmental factors including chromosomal translocations and mutation, ionising radiation, and chemicals. Due to its heterogeneity, it remains a fatal and incurable disease. With the aim of developing better treatments and designing better therapeutics for this disease, a better understanding of the genetic makeup of AML cells is warranted.

Our longterm goal is to understand the role of Tribbles in the pathogenesis of AML. Tribbles proteins, of which three mammalian homologues are known, have a variety of functions in development and homeostasis that include roles in proliferation, survival, motility, and metabolism. We were the first to show that TRIB2 overexpression lead to AML through inactivation of C/EBPa, an important transcription factor responsible for granulocytic differentiation and blocking of cellular proliferation, characteristic of AML. We identified Tribbles homologue 2 (Trib2) as a Notch-regulated transcript in leukemic cells undergoing growth arrest in T cell acute lymphoblastoc leukaemia (T-ALL). C/EBPalpha gene dysregualtion and mutation are common features of AML, and NOTCH1 mutaitons are commonly found in T-ALL. This project aimed to investigate the role of TRIB2 in acute leukaemia, with a view to the advancement of potential targeted therapy.

Our work has identified Trib2 in a complex with C/EBP alpha which resulted in C/EBP alpha inhibition and degradation. We have identified the regions of the TRIB2 gene that are required and necessary for the induction of leukaemia, and have linked this to the requirement for TRIB2-induced degradation of C/EBP alpha. We have shown that of the three TRIB family members, TRIB1 and TRIB2 function similarly, whereas TRIB3 does not function in a similar way in the study of AML. Functionally, we have shown that TRIB2 functions to degrade its target proteins specifically in the proteasome pathway mediated via ubiquitination. Site specific residues for these interactions in the degradation pathway have been identified. We have identified a network involving C/EBP alpha p42 and p30 dominant negative in Trib2 mediated leukemogenesis. This work in ongoing and being performed in collabouration with experts in the C/EBP alpha field. We have also delineated Trib2 in T-ALL and cooperation with NOTCH1 mutation. TRIB2 appears to uniquely identify a T-cell genetic signature, and the significance of this is of interest for further study.

In summary, this project has resulted, thus far, in three publications in peer- reviewed journals, which contribute significantly to our understanding of Tribbles proteins in AML and ALL. This work has led to collabourative efforts between this research group and groups in Denmark, the United Kingdom, and the United States of America. We anticipate that our findings will not only lead to a better understanding of the pathogenesis of AML and ALL, but will also have direct translational utility as they will identify new targets for diagnosing, monitoring, and treating AML and ALL.