Generation of rac3 null mutant mice:: Role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia
Generation of rac3 null mutant mice:: Role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia
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DOI：
10.1128/mcb.25.13.5777-5785.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Heisterkamp, N
中科院分区：
文献类型：
--
作者：
Cho, YJ;Zhang, B;Heisterkamp, N
许多研究间接地暗示Rac GTP酶与癌症有关。为了研究Rac 3是否有助于正常或恶性细胞功能，我们通过基因靶向产生了Rac 3无效突变体。这些小鼠存活、可生育，并且缺乏明显的外部表型。这表明Rac 3功能对于胚胎发育是不可或缺的。Bcr/Abl是一种失调的酪氨酸激酶，可引起人类慢性髓细胞性白血病和Ph阳性急性淋巴细胞性白血病。Vav 1是Rac的造血特异性交换因子，在Bcr/Abl P190转基因小鼠的原发性淋巴瘤中呈组成性酪氨酸磷酸化，表明Rac活化不当。rac 3在这些恶性造血细胞中表达。使用来自表达或缺乏rac 3的BCR/ABL转基因小鼠的裂解物，我们在恶性前体B系淋巴母细胞中检测到活化的Rac 3的存在，而不是Rac 1或Rac 2。此外，在雌性P190 BCR/ABL转基因小鼠中，缺乏rac 3与较长的平均生存期相关。这些数据首次直接显示Rac在体内白血病中的刺激作用。此外，我们的数据表明，干扰Rac 3活性，例如，通过使用香叶基-香叶基转移酶抑制剂，可以为Ph阳性急性淋巴细胞白血病患者提供积极的临床益处。
Numerous studies indirectly implicate Rac GTPases in cancer. To investigate if Rac3 contributes to normal or malignant cell function, we generated rac3 null mutants through gene targeting. These mice were viable, fertile, and lacked an obvious external phenotype. This shows Rac3 function is dispensable for embryonic development. Bcr/Abl is a deregulated tyrosine kinase that causes chronic myelogenous leukemia and Ph-positive acute lymphoblastic leukemia in humans. Vav1, a hematopoiesis-specific exchange factor for Rac, was constitutively tyrosine phosphorylated in primary lymphomas from Bcr/Abl P190 transgenic mice, suggesting inappropriate Rac activation. rac3 is expressed in these malignant hematopoietic cells. Using lysates from BCR/ABL transgenic mice that express or lack rac3, we detected the presence of activated Rac3 but not Rac1 or Rac2 in the malignant precursor B-lineage lymphoblasts. In addition, in female P190 BCR/ABL transgenic mice, lack of rac3 was associated with a longer average survival. These data are the first to directly show a stimulatory role for Rac in leukemia in vivo. Moreover, our data suggest that interference with Rac3 activity, for example, by using geranyl-geranyltransferase inhibitors, may provide a positive clinical benefit for patients with Ph-positive acute lymphoblastic leukemia.