The mixed-lineage leukaemia gene (MLL) was found to form a variety of chromosomal translocations each resulting in the pathogenesis of acute myeloid and lymphoid leukaemia. Although these cytogenetic abnormalities were discovered over thirty years ago, little is known about the biochemical functions of MLL or how its translocations results in the development of leukaemia. The translocation partners of MLL share very little sequence or seemingly functional similarities. However, their translocations result in up-regulation of several genes within the Hox cluster and therefore the pathogenesis of leukaemia. To define the molecular reason why these translocations result in leukaemogenesis, my co-authors and I purified several of the commonly occurring MLL chimeras. We have identified many of the MLL partners within a novel super elongation complex (SEC), including ELL, P-TEFb and AFF4. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 within SEC in leukaemic cells shows reduction in MLL chimera target gene expression suggesting that AFF4 could be a key regulator in the pathogenesis of leukaemia through many of the MLL partners. We are in the process of identifying downstream targets of SEC in normal and leukaemic cells in the hope of developing targeted therapeutic for MLL translocation based leukaemia.

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