Translocations of the mixed lineage leukaemia (MLL) gene occur in 60-80% of all infant acute leukaemia’s identified with a poor prognosis. MLL-AF9 induces aberrant expression of epigenetic target genes resulting in leukemic transformation. Epigenetic modifications provide a plausible biological relevance for the treatment of MLL-AF9 through the inhibition of methyltransferases (eg DOT1L) and histone deacetylases (HDAC). Furthermore, the amplified activity of CDK’s primarily due to the loss of endogenous CDK inhibitors or increased expression of cellular cyclins have been identified as critical factors leading to the loss of cell cycle control. Using retroviral gene transduction of hematopoietic stem cells we have developed preclinical mouse models that offer acute leukaemia driven by MLL-AF9 +/- the oncogenic driver NRASG12D. In order to identify key molecular targets for the treatment of this aggressive disease we conducted a small molecule inhibitor candidate screen to test the efficacy of pharmacological agents. CDK inhibitor, Dinaciclib, identified itself as a potent inducer of apoptosis in contrast to conventional chemotherapies used to treat this disease as well as recently published novel targeted therapies (Dot1L inhibitor, EPZ004777, Brd3/4 inhibitor, JQ1 and HDAC inhibitor, panobinostat). Dinaciclib is a superior pan cyclin-dependent kinase inhibitor with a high affinity to CDK9. It is known that MLL-AF9 recruits positive transcription elongation factor b (pTEFb), a dimer of cyclin T / CDK9, as the key enzymatic component leading to RNA polymerase II phosphorylation. Cell based assays demonstrated drug specificity confirming a reduction in Ser-2 phosphorylation of RNA polymerase II. Importantly, the growth inhibitory and pro-apoptotic effects of Dinaciclib corresponded with its predicted potency for CDK9 inhibition (IC50 for apoptosis ~15nM at 24hrs) of murine MLL-AF9 cells and human MLL-AF9 cell line, THP-1. Ultimately, Dinaciclib was well tolerated in vivo where it delayed the progression of MLL-AF9 tumour burden and significantly prolonged survival of those mice. We propose that Dinaciclib will have potent and selective activity as a clinical candidate in poor-prognosis MLL-AF9 patient settings.