Constitutively active MEK1 expression driven by the myeloid-selective MRP8 promoter induces epithelial hyperplasia and papilloma formation.

The mitogen-activated protein kinase kinase (MEK)/extracellular-regulated kinase (ERK) signaling pathway is hyperactivated in myeloid leukemias characterized by differentiation blockade, suggesting a potential role in disruption of myeloid differentiation. However, other reports indicate that MEK/ERK activation is required for normal myeloid differentiation. To investigate the in vivo role of MEK/ERK hyperactivation in myeloid differentiation and leukemia development we generated transgenic mice with doxycycline (DOX)-inducible expression of constitutively active MEK1 (CA-MEK1) under the control of the myeloid-selective MRP8 promoter. Two independent transgenic lines (lines A and B) were generated. Strikingly, both lines developed epithelial abnormalities following DOX induction of CA-MEK1. Line A mice exhibited pervasive skin/epithelial thickening, while line B mice developed papillomas. Prominent induction of CA-MEK1 was detected in epidermis, but not dermis, and was accompanied by epithelial cell hyperplasia. Line B mice also exhibited CA-MEK1 induction and ERK1/2 phosphorylation/activation in bone marrow and blood. Induction of CA-MEK1 over a range of 8-33 weeks, however, failed to alter the frequency of monocytes and granulocytes in the blood of line B mice. Collectively, our findings demonstrate that the MRP8 promoter is active in both myeloid and epithelial tissues. Moreover, we confirm earlier reports that hyperactivation of MEK/ERK signaling in epithelial tissues promotes epithelial hyperplasia. In addition, our findings indicate that hyperactivation of the MEK/ERK pathway alone is insufficient to alter myeloid differentiation and initiate leukemia development. We propose that MEK/ERK hyperactivation likely acts to promote proliferation or cell survival in leukemias where differentiation has been blocked by other genetic or epigenetic events.