Stein Eytan M, Tallman Martin S
Leukemia Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.
Curr Opin Hematol. 2015 Mar;22(2):92-6. doi: 10.1097/MOH.0000000000000123.
The 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.
The 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.
Acute 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.
本研究旨在探讨在理解涉及混合谱系白血病（MLL）基因易位的白血病发病机制方面的最新进展以及这些发现的治疗意义。
过去5年出现了一系列临床研究，近期已阐明MLL重排白血病的发病机制。基于这些研究，已启动一项针对组蛋白甲基转移酶DOT1L的1期临床试验，并于2014年12月在美国血液学会年会上报告了中期临床结果。
急性白血病，无论是髓系还是淋系，若在染色体位点11q23处存在涉及MLL基因的易位，即使进行异基因骨髓移植，预后也很差。MLL易位白血病的发病机制最近与组蛋白甲基转移酶DOT1的异常活性相关。用强效、选择性抑制剂抑制DOT1L的临床前研究已表明在动物模型中成功根除白血病克隆。基于这些研究，已启动一项使用DOT1L抑制剂EPZ - 5676的1期人体首次临床试验。
