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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1420-1428.
Prepublished online as a Blood First Edition Paper on May 29, 2007; DOI 10.1182/blood-2007-02-071761.
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Submitted February 1, 2007
Accepted May 23, 2007
Activation of MEK/ERK signaling pathway is involved in the myeloid lineage commitment
Chia-Lin Hsu, Kazu Kikuchi, and Motonari Kondo*
Department of Immunology, Duke University Medical Center, Durham, NC, United States
* Corresponding author; email: motonari.kondo{at}duke.edu.
Common lymphoid progenitors (CLPs) are lymphoid-lineage-committed progenitor cells. However, they maintain a latent myeloid differentiation potential that can be initiated by stimulation with IL-2 via ectopically expressed IL-2 receptors. Although CLPs express IL-7 receptors, which share the common  chain with IL-2 receptors, IL-7 cannot initiate lineage conversion in CLPs. In this study, we demonstrate that the critical signals for initiating lineage conversion in CLPs are delivered via IL-2R intracellular domains. Fusion of the A region of the IL-2R cytoplasmic tail to IL-7R enables IL-7 to initiate myeloid differentiation in CLPs. We found that Shc, which associates with the A region, mediates lineage conversion signals through the MAPK pathway. Since MEK/ERK inhibitors completely blocked IL-2-mediated lineage conversion, MAPK activation, specifically via the MEK/ERK pathway, is critically involved in the initiation of this event. Furthermore, formation of granulocyte/macrophage (GM) colonies by hematopoietic stem cells (HSCs), but not by common myeloid progenitors (CMPs), was severely reduced in the presence of MEK/ERK inhibitors. These results demonstrate that activation of MEK/ERK plays an important role in GM lineage commitment.
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