Opposing Roles for MEK/ERK in Differentiation & Leukemia

描述（由申请人提供）：髓系白血病的特征是由于白血病癌蛋白（如PML/RAR-α）的表达而导致的分化异常阻断。阐明负责正常骨髓分化的机制将进一步加深我们对白血病分化阻滞的理解，并促进新的分化疗法的发展。因此，我们的长期目标是确定导致髓样分化的细胞内信号通路，以及这些通路在白血病发生中的作用。在初步研究中，我们观察到在髓样分化过程中MEK/ERK信号转导通路的快速和长期激活。此外，MEK/ERK活化是骨髓细胞系分化所必需的。这与MEK/ERK活化在增殖和存活中的已知作用以及髓性白血病中的组成性MEK/ERK过度活化形成对比。总之，这些研究表明MEK/ERK激活的作用二分法：在正常条件下促进分化，在分化受阻的条件下转化。因此，我们推测MEK/ERK通路的长期激活对于苦参碱诱导的髓样分化至关重要。我们进一步假设MEK/ERK通路的激活与分化抑制白血病癌蛋白协同促进白血病发生。为了验证这一假设，我们将：1）阐明MEK/ERK活化在精氨酸诱导的骨髓细胞系和正常小鼠骨髓祖细胞的原代培养物的骨髓分化过程中的重要性; 2）确定MEK/ERK活化在精氨酸诱导的骨髓分化过程中的功能后果; 3）检查MEK/ERK激活通过产生可诱导表达组成型活性MEK酶的转基因小鼠促进体内髓系分化，髓系细胞;和4）确定MEK/ERK活化是否与PML/RAR-α的表达协同促进髓性白血病发生。

DESCRIPTION (provided by applicant): Myeloid leukemias are characterized by aberrant blockade of differentiation due to expression of leukemic oncoproteins such as PML/RAR-alpha. Elucidation of the mechanisms responsible for normal myeloid differentiation will further our understanding of differentiation blockades in leukemias, and foster the development of novel differentiation therapies. Thus, our long-term objective is to define the intracellular signaling pathways that lead to myeloid differentiation, and the role these pathways play in leukemogenesis. In preliminary studies we have observed rapid and prolonged activation of the MEK/ERK signal transduction pathway during myeloid differentiation. Furthermore, MEK/ERK activation was required for differentiation in myeloid cell lines. This contrasts with known roles for MEK/ERK activation in proliferation and survival, and constitutive MEK/ERK hyperactivation in myeloid leukemias. Together, these studies suggest a dichotomy of roles for MEK/ERK activation: promoting differentiation under normal conditions, and transformation under conditions where differentiation is blocked. Therefore, we hypothesize that prolonged activation of the MEK/ERK pathway is critically important for cytokine-induced myeloid differentiation. We further hypothesize that activation of the MEK/ERK pathway cooperates with differentiation-inhibiting leukemic oncoproteins to promote leukemogenesis. To test this hypothesis, we will: 1) elucidate the importance of MEK/ERK activation during cytokine-induced myeloid differentiation of myeloid cell lines and primary cultures of normal murine myeloid progenitors; 2) determine the functional consequences of MEK/ERK activation during cytokine-induced myeloid differentiation; 3) examine whether MEK/ERK activation promotes myeloid differentiation in vivo through the generation of transgenic mice that inducibly express constitutively active MEK enzyme in myeloid lineage cells; and 4) determine whether MEK/ERK activation cooperates with expression of PML/RAR-alpha to promote myeloid leukemogenesis.