Opposing Roles for MEK/ERK in Differentiation & Leukemia

髓系白血病的特征是由于白血病的表达而异常地阻止分化 癌蛋白如PML/RAR-α。正常髓系发病机制的阐明 分化将加深我们对白血病分化障碍的理解，并促进 开发新的辨证治疗方法。因此，我们的长期目标是定义细胞内 导致髓系分化的信号通路，以及这些通路在白血病发生中所起的作用。 在初步研究中，我们观察到MEK/ERK信号的快速和持续激活 髓系分化中的信号转导途径。此外，需要激活MEK/ERK以 髓系细胞系的分化。这与已知的MEK/ERK激活在细胞增殖中的作用形成对比 髓系白血病的生存和组成性MEK/ERK高激活。总而言之，这些研究 提出了MEK/ERK激活的两种角色：在正常情况下促进分化， 以及在分化受阻的条件下进行转化。因此，我们假设 MEK/ERK通路的长时间激活对细胞因子诱导的髓样细胞至关重要 差异化。我们进一步假设，MEK/ERK通路的激活与 抑制白血病癌蛋白的分化以促进白血病的发生。为了验证这一假设，我们将： 1)阐明MEK/ERK活化在细胞因子诱导骨髓细胞分化过程中的重要性 髓系细胞系和正常小鼠髓系祖细胞的原代培养；2)测定功能 细胞因子诱导髓系分化过程中MEK/ERK激活的后果；3)检查 MEK/ERK激活通过产生转基因小鼠促进体内髓系分化 在髓系细胞中诱导表达具有结构性活性的MEK酶；以及4)确定 MEK/ERK激活与PML/RAR-α表达协同促进髓系白血病的发生。

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.