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Blood:对抗白血病的新分子靶标

来源:生物谷 2014-05-08 13:13

2014年5月8日讯 /生物谷BIOON/--近日,昆士兰大学研究人员发现一种分子“靶标”,可能有助开发新的药物来对抗白血病。

急性髓系白血病细胞

Tom Gonda教授团队已经发现,Myb蛋白与另一种蛋白p300的“对接”互作部位,Myb蛋白与蛋白p300的相互作用对于急性髓系白血病是至关重要的。

研究数据标识出Myb-p300相互作用的关键作用,并表明破坏这种相互作用可能导致潜在的治疗策略。

这一发现可能会导致团队开发一种药物来阻止这种互动,以此不仅能停止急性髓系白血病细胞的生长,同时也可能阻断其他类型白血病细胞的生长。

研究人员解释:Myb蛋白是由MYB致癌基因产生,MYB基因有导致癌症的潜能,对于白血病细胞的持续增长是必需的。

不过,值得注意的是,MYB对于正常血细胞的形成也是必不可少的,所以针对此基因的同时,注意不能完全破坏正常血细胞的产生。新研究表明,即使在​​MYB-p300的相互作用无法发生时,正常血细胞仍可继续形成,这表明药物阻止相互作用可能是安全的。

Gonda教授表示,由于Myb蛋白不是药物的常规靶标,团队也将研究其他的方法来“瞄准”MYB,如针对MYB下游基因和蛋白质。如果我们能阻止MYB控制的下游分子,可能会得到同样的结果。(生物谷Bioon.com)

 

Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes

Diwakar R. Pattabiraman, Crystal McGirr, Konstantin Shakhbazov, Valerie Barbier, Keerthana Krishnan, Pamela Mukhopadhyay, Paula Hawthorne, Ann Trezise, Jianmin Ding, Sean M. Grimmond, Peter Papathanasiou, Warren S. Alexander, Andrew C. Perkins, Jean-Pierre Levesque, Ingrid G. Winkler, and Thomas J. Gonda.

The MYB oncogene is widely expressed in acute leukemias and is important for the continued proliferation of leukemia cells, suggesting that MYB may be a therapeutic target in these diseases. However, realization of this potential requires a significant therapeutic window for MYB inhibition, given its essential role in normal hematopoiesis, and an approach for developing an effective therapeutic. We previously showed that the interaction of c-Myb with the coactivator CBP/p300 is essential for its transforming activity. Here, by using cells from Booreana mice which carry a mutant allele of c-Myb, we show that this interaction is essential for in vitro transformation by the myeloid leukemia oncogenes AML1-ETO, AML1-ETO9a, MLL-ENL, and MLL-AF9. We further show that unlike cells from wild-type mice, Booreana cells transduced with AML1-ETO9a or MLL-AF9 retroviruses fail to generate leukemia upon transplantation into irradiated recipients. Finally, we have begun to explore the molecular mechanisms underlying these observations by gene expression profiling. This identified several genes previously implicated in myeloid leukemogenesis and HSC function as being regulated in a c-Myb-p300-dependent manner. These data highlight the importance of the c-Myb-p300 interaction in myeloid leukemogenesis and suggest disruption of this interaction as a potential therapeutic strategy for acute myeloid leukemia.

 

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