Targeting Reptin Function in Acute Myeloid Leukaemia

Acute myeloid leukaemia (AML) is characterized by the rapid growth of immature white blood cells, which accumulate in the bone marrow and are not able to differentiate into normal functioning cells. Despite recent advances in AML therapy, cytogenetically defined subgroups with poor prognosis are still prevalent. Chromosomal translocations, which encode abnormal fusion proteins, are common in patients with AML, and the MLL (Mixed Lineage Leukaemia) locus is the most frequently rearranged in paediatric AML. Previous studies in our laboratory used global gene expression analysis in conditionally immortalized MLL-rearranged mouse myeloid cells to demonstrate that the Reptin gene was positively regulated by MLL-fusion genes. Reptin (also known as RUVBL2), together with its related family member Pontin (also known as RUVBL1), functions as part of multi-protein complexes involved in chromatin remodelling, DNA repair, regulation of transcription and ribonucleoprotein assembly. Further work in our laboratory found Reptin to be essential for sustaining the hyperproliferative state and clonogenic potential, as well as suppressing apoptosis, of human AML cells, both MLL-rearranged and non-MLL rearranged. Here, we present our recent data, investigating the transcriptional pathways regulated by Reptin in order to identify clinically approved drugs that can modulate these pathways, and using xenotransplantation assays to establish the efficacy of targeting Reptin in vivo. Our preliminary results indicate that Reptin regulates the function of the oncoprotein c-MYC in human AML cell lines and represents an exciting novel candidate target for the therapy of human AML.