MEK kinase 1 is essential for Bcr–Abl-induced STAT3 and self-renewal activity in embryonic stem cells

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Abstract
BCR–ABL oncogene, the molecular hallmark of chronic myelogenous leukemia, arises in a primitive hematopoietic stem cell that has the capacity for both differentiation and self-renewal. Its product, Bcr–Abl protein, has been shown to activate signal transducers and activators of transcription 3 (STAT3) and to promote self-renewal in embryonic stem (ES) cells, even in the absence of leukemia inhibitory factor (LIF). MEK kinase 1 (MEKK1) is a 196-kDa mitogen-activated protein kinase (MAPK) kinase kinase involved in Bcr–Abl signal 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 key role in Bcr–Abl-induced STAT3 activation and in ES cells’ capacity for LIF-independent self-renewal, and may thus be involved in Bcr–Abl-mediated leukemogenesis in stem cells.