The Role of MEK Kinase 1 in Bcr-Abl-Induced Seｌｆ-Renewal Activity of Embryonic Stem Cells

Creators Nakamura Yukinori

Creators Yujiri Toshiaki

Creators Tanizawa Yukio

BCR-ABL oncogene, the moecular hallmark of chronic mylogenous leukemia, arises in a promitive hematopoietic stem cell that has the capacity for both differentiation and self-renewal. Its product, Bcr-Abl protein, has been shown to sctivate signal transducers and activators of transcription 3 (STAT3) and to promote self-renewal in embryonic stem (ES)cells, even in the absencs of leukemia in hibitory factor (LIF). MEK kinase 1 (MEKK1) is a 196-kDa mitogen-activated protein kinase (MAPK) kinase kinase involoved in Bcr-Ablsignal transduction. To investigate the role of MEKK1 in bcr-Abl-induced transformation of stem cells, p210 Bcr-Abl was stably transfected into wild type (WTp210)and MEKK1-/-(MEKK1-/-p210) ES cells. Bcr-Abl enhanced MEKK1 expression in ES transfectants, as it does in other Bcr-Abl-transformed cells. In the absence of LIF, WTp210 cells showed constitutive STAT3 activation and formed rounded, compact colonies having strong alkaline phosphatase activity, a characteristic phenotype of undifferentiated ES cells. MEKK1-/-p210 cells, by contrast, showed less STAT3 activity than WTp210 cells and formed large, flattened colonies having weak alkaline phosphatase activity, a phenotype of differentiated ES cells. These results indicate that MEKK1 plays a ker role in Bcr-Abl-induced STAT3 activation and in ES cells's capacity for LIF-independent self-renewal, and may thus be involved in Bcr-Abl-mediated leukemogenesis in stem cells.

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