德國(guó)埃朗根－紐倫堡大學(xué)24日發(fā)表公報(bào)說(shuō),，他們從基因角度揭示了一種名為“混合系白血病”（MLL）的小兒急性白血病致病機(jī)理,，為治療這種病帶來(lái)新希望,。
研究人員在最新一期美國(guó)《公共科學(xué)圖書(shū)館·生物學(xué)》雜志上報(bào)告說(shuō),，基因的表達(dá)需要得到準(zhǔn)確調(diào)控,，才能使機(jī)體保持適當(dāng)?shù)墓δ?。如果調(diào)控出現(xiàn)異常,，就會(huì)導(dǎo)致錯(cuò)誤的基因表達(dá)，從而引起細(xì)胞癌變等嚴(yán)重后果,。
研究人員發(fā)現(xiàn),，引起“混合系白血病”的異常融合蛋白能夠“挾持”一類基因調(diào)控物質(zhì)，導(dǎo)致HOXA基因和MEIS1基因異常表達(dá),。在胚胎干細(xì)胞向造血細(xì)胞分化過(guò)程中,，上述兩種基因的表達(dá)本應(yīng)受到抑制，以使造血細(xì)胞分化成熟,，但受異常融合蛋白的影響,，這些基因卻始終進(jìn)行表達(dá)，影響造血細(xì)胞分化,，從而導(dǎo)致白血病,。
研究人員說(shuō)，對(duì)上述致病機(jī)理的理解幫助他們找到了一些能抑制異常融合蛋白的化學(xué)制劑,。目前研究人員正對(duì)這些制劑進(jìn)行試驗(yàn),，以確認(rèn)其治療混合系白血病的效果。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
