Src family kinases and the MEK/ERK pathway in the regulation of myeloid differentiation and myeloid leukemogenesis

The production of mature monocytes/macrophages and granulocytes via myeloid differentiation is a central component of the host defense mechanism against invading microorganisms. However, in myeloid leukemias genetic changes lead to blockade of myeloid differentiation. When this happens, immune responses can become severely impaired and the accumulation of proliferative blasts causes bone marrow crowding and onset of symptomatic leukemia. There is considerable hope that molecular targeting of specific signaling pathways and proteins will prove to be a viable strategy for restoring differentiation potential in myeloid leukemias. Indeed, in acute promyelocytic leukemia, treatment with ATRA can overcome the differentiation blockade and is an effective curative approach. To devise strategies and reagents that can be used to induce differentiation in other myeloid leukemias, it is important to gain an understanding of the molecular pathways that drive the normal differentiation process. Emerging evidence implicates both Src family kinases and the MEK/ERK pathway in regulating myeloid differentiation. It is interesting that Src family kinases appear to be negative regulators of myelopoiesis, while the MEK/ERK pathway is an important positive regulator of both monocytic and granulocytic differentiations. This suggests that pharmacologic inhibitors of SFKs may be of value in restoring or enhancing myeloid differentiation. In this regard, the SFK inhibitor dasatinib has recently been approved by the FDA for use in imatinib-resistant CML. Evaluation of dasatinib, alone or in combination with differentiation inducers, in the treatment of differentiation-defective AML seems warranted. The important role that the MEK/ERK pathway plays in promoting myeloid differentiation appears to conflict with observations that the MEK/ERK pathway is hyperactivated or overexpressed in a majority of primary AMLs. Moreover, pharmacologic inhibition of the MEK/ERK pathway in AML results in the induction of apoptosis, indicating that MEK/ERK activation is important for the survival of AML cells. Collectively, these data suggest that the MEK/ERK pathway may play more than one role in myeloid lineage cells, depending on the cellular context. In normal myeloid cells, activation of the MEK/ERK pathway is important for promoting differentiation. However, when differentiation becomes blocked, as is the case in most AMLs, MEK/ERK activation can no longer drive differentiation, and instead begins to support cellular survival or proliferation. Thus, therapeutic strategies aimed at provoking myeloid differentiation in AML by stimulating the MEK/ERK pathway are unlikely to be successful unless the differentiation blockade is simultaneously relieved. © 2007 Elsevier Ltd. All rights reserved.