Novel therapies that target Rap1 could potentially be used to treat leukemias caused by BCR/ABL

11-10-2006

"The Ras family small GTPase Rap1 is activated by hematopoietic cytokines, such as interleukin (IL)-3, to induce beta 1 integrin-mediated cell adhesion or by the BCR/ABL fusion tyrosine kinase to stimulate the MEK/Erk signaling pathway. Here, we demonstrate that the abrogation of Rap1 activation by SPA-1, a Rap1-specific GAP, inhibits activation of B-Raf, MEK, Erk, and Akt in a murine hematopoietic cell line, Ton.B210, stimulated with IL-3 or inducibly expressing BCR/ABL," scientists writing in the journal Oncogene reported.

"Furthermore, Rap1 inactivation had an inhibitory effects on proliferation and survival of Ton.B210 cells, which were more remarkable when cells were stimulated by BCR/ABL than by IL-3," explained A. Jin and colleagues, Tokyo Medical & Dental University. "Induction of BCR/ABL expression increased adhesion of Ton.B210 cells to fibronectin in a manner at least partly dependent on its kinase activity, and Rap1 inhibition by SPA-1 partially inhibited BCR/ABL-induced adhesion of cells.

"Thus, IL-3- or BCR/ABL-induced activation of Rap1 may play important roles in regulation of cell proliferation and survival through activation of the B-Raf/MEK/Erk and Akt signaling pathways and in induction of integrin-mediated cell adhesion."

The researchers concluded, "Furthermore, as compared with IL-3, BCR/ABL is more dependent on Rap1-mediated signaling to induce cell proliferation and survival and, thus, Rap1 may represent an attractive target for novel therapies for leukemias caused by BCR/ABL."

Jin and colleagues published their study in Oncogene (BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion. Oncogene, 2006;25(31):4332-4340).

Additional information can be obtained by contacting O. Miura, Tokyo Medical & Dental University, Dept. of Hematology, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138519, Japan.

This article was prepared by Cancer Gene Therapy Week editors from staff and other reports. Copyright 2006, Cancer Gene Therapy Week via NewsRx.com.