Opposing Roles for MEK/ERK in Differentiation & Leukemia

描述（由申请人提供）：髓系白血病的特点是由于白血病癌蛋白如PML/ rar - α的表达而异常阻断分化。阐明正常髓细胞分化的机制将进一步加深我们对白血病分化阻断的理解，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细胞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，我们观察到髓细胞分化过程中MEK/ERK信号转导通路的快速和长时间激活。此外，髓系细胞分化需要MEK/ERK活化。这与已知的MEK/ERK激活在增殖和存活中的作用，以及在髓性白血病中的组成性MEK/ERK过度激活形成对比。综上所述，这些研究表明MEK/ERK激活的双重作用：在正常条件下促进分化，在分化受阻的条件下转化。因此，我们假设延长MEK/ERK通路的激活对于细胞因子诱导的髓细胞分化至关重要。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。为了验证这一假设，我们将：1)阐明MEK/ERK激活在细胞因子诱导的髓系分化和正常小鼠骨髓祖细胞原代培养中的重要性；2)确定细胞因子诱导的髓细胞分化过程中MEK/ERK活化的功能后果；3)通过在髓系细胞中诱导表达组成型活性MEK酶的转基因小鼠，研究MEK/ERK激活是否能促进体内髓系分化；4)确定MEK/ERK活化是否与PML/ rar - α表达协同促进髓性白血病的发生。

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.