预测白血病患者预后的蛋白也可能成为治疗靶点

2010年7月8日

剑桥，群众。•怀特海研究所的研究人员和波士顿儿童医院已经发现一种蛋白质，称为武藏2，这是预测预后急性髓细胞性白血病（AML）和慢性粒细胞性白血病（慢性粒细胞白血病）患者。

高水平的武藏2蛋白与细胞增殖增加，降低细胞的成熟，和多种癌症相关的细胞信号通路在人类白血病。根据研究人员的文章，该蛋白和细胞功能在某些类型的白血病中可能是潜在的治疗靶点自然医学。

白血病, blood 癌症 characterized by an overgrowth of certain blood cells, is diagnosed in an estimated 48,000 new patients annually。 In AML and CML, a cell type in the bone marrow becomes defective, dividing repeatedly and eventually crowding out normal red and white blood cells, leading to贫血and an inability to fight infections。

AML progresses very quickly, and, if untreated by chemotherapy or bone marrow transplant, results in death。 CML's beginning phase is much milder until the number of immature blood cells, called blast cells, suddenly increases-an occurrence known as blast crisis。 Some drug therapies, such as Gleevec, may help treat patients in the early phase and even the blast phase of CML, but only a bone marrow transplant is considered curative。

像其他癌症cells, AML and CML cells proliferate more rapidly and are more resistant to routine programmed cell death than normal cells。 Although each type of 癌症 has a different genetic or biochemical method for reproducing and staying alive, sometimes there are common threads that bind some 癌症 types together。

For AML and CML, one of those threads is Musashi 2, a protein that regulates other proteins' production by binding to their RNA templates。

科学家米迦勒和克里斯托弗lengner卡拉斯，第一作者自然医学article, examined Musashi 2's function in established cell lines from AML and CML patients, mouse models of AML and CML, and gene expression data from 600 AML and CML patients。

All of the data pointed to Musashi 2 playing an integral role in AML and during the blast crisis stage of CML。

"It seems like Musashi 2 on its own is not sufficient to cause the 癌症-there is another genetic hit that must first occur to initiate the 癌症," says Lengner, who is a postdoctoral researcher in the lab of Whitehead Institute Founding Member and MIT biology professor Rudolf Jaenisch。 "And if you then add Musashi 2, it makes the 癌症 more stem cell-like, and as a consequence of that, much more aggressive。"

Kharas's and Lengner's experiments showed a direct correlation between increased Musashi 2 levels and increased aggressiveness of the 癌症。 When the researchers reduced the amount of Musashi 2 in AML and CML cell lines, the 癌症s were less aggressive, and in some cases, matured and even underwent programmed cell death。 When they examined patient data, Kharas and Lengner found that patients with high levels of Musashi 2 had poorer outcomes than did patients with lower Musashi 2 levels。

"It's actually very amazing," says Kharas, who is is an instructor at Brigham and Women's Hospital and a researcher in the 波士顿儿童医院 lab ofGeorge Daley。 "Everyone says that human cell lines have nothing to do with human patients。 But, we could go from a mouse, to an in vitro cell culture model, to patient data。 And when we saw that you could reduce Musashi 2 in these cell lines and use that information to predict the survival of patients, we were really impressed。"

Although Musashi 2 has been the subject of little research, it is known to regulate a self-renewing pathway in stem cells as well as a cell-proliferation pathway。 To see what cellular pathways Mushasi 2 is affecting in human leukemia cells, Kharas and Lengner analyzed the genes expressed in those cells compared with the genes expressed in leukemia cells whose Musashi 2 expression had been turned down。 The top targets turned on by Musashi 2 reads like a who's who of cellular pathways associated with 癌症: Wnt, Ras-Mapk, and Myc, among others。

In the future, Kharas and Lengner say that controlling Musashi 2 expression or its targets may lead to new therapies for leukemia patients。 Daley agrees。

“我们对某些类型的白血病取得了长足的进展，但仍然是高度致命的白血病，”Daley说，主任的干细胞移植计划at 波士顿儿童医院 and a former Whitehead Institute Fellow。 "We've linked a new gene to the most aggressive leukemias, which is immediately helpful in identifying patients with good and bad prognoses。 We are hopeful our new insights into leukemia will help us identify new drug targets。"

这项研究得到了支持国立卫生研究院（NIH），该白血病 and Lymphoma Society，以及休斯霍华德医学研究所(HHMI)。

接触
妮科尔吉斯
617-258-6851
giese@wi。mit。edu

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