Opposing Roles for MEK/ERK in Differentiation & Leukemia

描述(申请人提供)：髓系白血病的特征是由于PML/RAR-α等白血病癌蛋白的表达而导致分化异常受阻。阐明导致正常髓系分化的机制将加深我们对白血病分化障碍的理解，并促进新的分化治疗方法的发展。因此，我们的长期目标是确定导致髓系分化的细胞内信号通路，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信号转导通路在髓系分化过程中迅速而持久的激活。此外，髓系细胞系的分化需要MEK/ERK的激活。这与已知的MEK/ERK激活在增殖和生存中的作用以及髓系白血病中结构性MEK/ERK过度激活的作用形成了鲜明对比。总之，这些研究提出了MEK/ERK激活的两种角色：在正常条件下促进分化，在分化受阻的条件下转化。因此，我们假设MEK/ERK通路的长时间激活对于细胞因子诱导的髓系分化至关重要。我们进一步假设，MEK/ERK通路的激活与抑制分化的白血病癌蛋白协同促进白血病的发生。为了验证这一假说，我们将：1)阐明MEK/ERK激活在细胞因子诱导的髓系细胞系和正常小鼠髓系祖细胞原代培养中的重要性；2)确定MEK/ERK激活在细胞因子诱导的髓系分化过程中的功能后果；3)检测MEK/ERK激活是否通过产生在髓系细胞中诱导表达有固有活性的MEK酶的转基因小鼠来促进体内的髓系分化；以及4)确定MEK/ERK激活是否与PML/RAR-α的表达协同促进髓系白血病的发生。

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.