德国埃朗根－纽伦堡大学24日发表公报说，他们从基因角度揭示了一种名为“混合系白血病”（MLL）的小儿急性白血病致病机理，为治疗这种病带来新希望。
研究人员在最新一期美国《公共科学图书馆·生物学》杂志上报告说，基因的表达需要得到准确调控，才能使机体保持适当的功能。如果调控出现异常，就会导致错误的基因表达，从而引起细胞癌变等严重后果。
研究人员发现，引起“混合系白血病”的异常融合蛋白能够“挟持”一类基因调控物质，导致HOXA基因和MEIS1基因异常表达。在胚胎干细胞向造血细胞分化过程中，上述两种基因的表达本应受到抑制，以使造血细胞分化成熟，但受异常融合蛋白的影响，这些基因却始终进行表达，影响造血细胞分化，从而导致白血病。
研究人员说，对上述致病机理的理解帮助他们找到了一些能抑制异常融合蛋白的化学制剂。目前研究人员正对这些制剂进行试验，以确认其治疗混合系白血病的效果。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS Biol 7(11): e1000249. doi:10.1371/journal.pbio.1000249
Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia
Dorothee Mueller, María-Paz García-Cuéllar, Christian Bach, Sebastian Buhl, Emanuel Maethner, Robert K. Slany*
Fusion proteins composed of the histone methyltransferase mixed-lineage leukemia (MLL) and a variety of unrelated fusion partners are highly leukemogenic. Despite their prevalence, particularly in pediatric acute leukemia, many molecular details of their transforming mechanism are unknown. Here, we provide mechanistic insight into the function of MLL fusions, demonstrating that they capture a transcriptional elongation complex that has been previously found associated with the eleven-nineteen leukemia protein (ENL). We show that this complex consists of a tight core stabilized by recursive protein–protein interactions. This central part integrates histone H3 lysine 79 methylation, RNA Polymerase II (RNA Pol II) phosphorylation, and MLL fusion partners to stimulate transcriptional elongation as evidenced by RNA tethering assays. Coimmunoprecipitations indicated that MLL fusions are incorporated into this complex, causing a constitutive recruitment of elongation activity to MLL target loci. Chromatin immunoprecipitations (ChIP) of the homeobox gene A cluster confirmed a close relationship between binding of MLL fusions and transcript levels. A time-resolved ChIP utilizing a conditional MLL fusion singled out H3K79 methylation as the primary parameter correlated with target expression. The presence of MLL fusion proteins also kept RNA Pol II in an actively elongating state and prevented accumulation of inhibitory histone methylation on target chromatin. Hox loci remained open and productive in the presence of MLL fusion activity even under conditions of forced differentiation. Finally, MLL-transformed cells were particularly sensitive to pharmacological inhibition of RNA Pol II phosphorylation, pointing to a potential treatment for MLL. In summary, we show aberrant transcriptional elongation as a novel mechanism for oncogenic transformation.
