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Mixed lineage rearranged leukaemia: pathogenesis and targeting DOT1L

Purpose of reviewThe purpose of this study is to explore the recent advances in understanding the pathogenesis of leukaemias with a translocation involving the mixed lineage leukaemia (MLL) gene and therapeutic implications of these discoveries. Recent findingsThe pathogenesis of MLL-rearranged leukaemias has recently been elucidated in a flurry of clinical studies that have appeared over the past 5 years. On the basis of these studies, a phase 1 clinical trial has been initiated targeting the histone methyltransferase DOT1L with interim clinical results reported at the American Society of Hematology Annual Meeting in December 2014. SummaryAcute leukaemia, both myeloid and lymphoid, that harbours a translocation involving the MLL gene at chromosome locus 11q23 has a poor prognosis, even with allogeneic bone marrow transplantation. The pathogenesis of MLL translocated leukaemias has recently been linked to aberrant activity of the histone methyltransferase DOT1. Preclinical studies of DOT1L inhibition with potent, selective inhibitors have shown successful eradication of the leukaemic clone in animal models. On the basis of these studies, a phase 1, first in man, clinical trial has been initiated with a DOT1L inhibitor, EPZ-5676.