Gadd45 stress sensors in leukemia

描述(申请人提供)：GADD45基因家族(Gadd45a，b，g)编码多种应激源快速诱导的细胞蛋白质，包括遗传毒性和致癌应激。GADD45蛋白作为癌基因感受器的独特作用已经在本实验室的几个新的肿瘤小鼠模型中被揭示出来，这表明GADD45可以通过拴住不同的信号通路而发挥肿瘤促进或抑制的作用。GADD45已被认为是致癌ras信号的中介体。RAS基因突变常见于血液系统恶性肿瘤，包括AML、MPD和MDS。最近的证据表明，致癌的N-RAS、K-RAS和H-RAS在小鼠中表现出不同的致白血病潜能，提示致癌的RAS引起的髓系白血病涉及独特的RAS信号网络，需要确定。另一方面，bcr-abl(BA)被认为是骨髓增殖性疾病(MPD)慢性粒细胞白血病(CML)中最常见的易位，激活的BA激酶癌蛋白影响细胞增殖和生存信号通路，包括RAS、PI3K、JAK-STAT和PDK2-NFkB。这些信号通路在慢性粒细胞白血病发病机制中的复杂性尚不完全清楚。最近，Gadd45a的表达在一组AML患者中被证明是改变的。我们的初步数据表明，Gadd45a在N-RAS驱动的白血病中作为癌基因发挥作用，而Gadd45a和Gadd45b在BA驱动的白血病中都作为肿瘤抑制基因发挥作用。此外，Gadd45a，b在人类CML中的表达也被观察到与疾病进展相关。GADD45蛋白作为致癌压力感受器调节癌基因驱动的白血病的作用尚未被研究，了解这些新的调节器在RAS和BCR-ABL分子病理学中的作用是重要的。为此，描述了两个特定的目标：目标1的目标是评估Gaddd45a如何调节RAS驱动的白血病致病性。子目标1A将确定Gadd45a缺失在体内RAS驱动的白血病转化中的作用~子目标1B旨在研究Gadd45a缺失在体外表达致癌RAS的骨髓中的作用~最后，子目标1C将分析人AML/MDS中激活的RAS、Gadd45a的变化以及Gadd45a功能改变调节的基因/通路。目的2旨在探索Gaddd45a，b肿瘤抑制因子功能如何影响BA驱动的白血病和信号转导。子目标2A将确定Gadd45a和Gadd45b功能缺失对BA驱动的白血病和伊马替尼治疗的影响~子目标2B将探索Gadd45a和Gadd45b的丢失如何影响BA的致癌潜力和体外的伊马替尼治疗~子目标2C将确定Gadd45a或Gadd45b在原发骨髓中获得的功能获得如何影响BA的致癌效应和伊马替尼治疗~最后，子目标2D将分析人类慢性粒细胞白血病Gadd45a和Gadd45b的变化以及Gadd45a和Gadd45b功能变化对基因/通路的不同调控。从拟议的研究中获得的知识应该会影响对白血病发生的理解，并增加对应激反应基因在其他癌症中所起作用的理解，并有助于开发新的/改进的癌症治疗方法。

DESCRIPTION (provided by applicant): Gadd45 family of genes (Gadd45a, b, g) encode for cellular proteins rapidly induced by multiple stressors, including genotoxic & oncogenic stress. The unique role of Gadd45 proteins as sensors of oncogenes has been born out by several novel cancer mouse models in this laboratory, indicating that, dependent on the activated oncogene, gadd45 can function as either tumor promoter or suppressor by tethering distinct signaling pathways. Gadd45 has been identified as a mediator of oncogenic ras signaling. Ras mutations occur frequently in hematopoietic malignancies, including in AML, MPD and MDS. Recent evidence indicates that oncogenic N-RAS, K-RAS, and H- RAS exhibit different leukemogenic potentials in mice, suggesting that myeloid leukemogenesis by oncogenic RAS involves unique RAS signaling networks that need to be determined. On the other hand, BCR-ABL (BA) is known as the most common translocation in the myeloproliferative (MPD) disorder chronic myelogenous leukemia (CML) where an activated BA kinase oncoprotein impacts on cell proliferation and survival signaling pathways including Ras, PI3K, JAK-STAT, and PDk2-NFkB. The complex nature of these signaling pathways in the pathogenesis of CML is not fully understood. Recently Gadd45a expression was documented to be altered in a subset of AML patients. Our preliminary data indicate that Gadd45a behaves as an oncogene in context of N-RAS driven leukemia whereas both Gadd45a & b function as tumor suppressors in context of BA-driven leukemia. Also, Gadd45a,b expression was observed to be altered in human CML correlating with disease progression. The role of Gadd45 proteins as oncogenic stress sensors that modulate oncogene driven leukemias has not been studied, and understanding the role of these novel modulators in the molecular pathology of RAS and BCR-ABL is important. To this end, two Specific Aims are delineated: Aim 1 is targeted at assessing how Gaddd45a modulates RAS driven leukemogenicity. Sub-aim 1A will ascertain the effect of loss of Gadd45a on RAS-driven leukemic transformation in vivo~ Sub-aim 1B is targeted at studying the effect of loss of Gadd45a in BM expressing oncogenic RAS in vitro~ finally Sub-aim 1C will analyze human AML/MDS for activated RAS, alterations in Gadd45a and genes/pathways regulated by altered Gadd45a function. Aim 2 is targeted at exploring how Gaddd45a,b tumor suppressor functions impact on BA-driven leukemia and signaling. Sub-aim 2A will ascertain the effect of loss of Gadd45a & b function on BA-driven leukemia and Imatinib treatment~ Sub-aim 2B will explore how loss of Gadd45a and Gadd45b impact on BA oncogenic potential and imatinib treatment in vitro~ Sub-aim 2C will ascertain how gain of function of Gadd45a or b in primary BM impacts on BA oncogenic effect and imatinib treatment~ and, finally, Sub-aim 2D will analyze human CML for alterations in Gadd45a and Gadd45b and genes/pathways differentially regulated by altered function of Gaddd45a & Gadd45b. Knowledge gained from the proposed research should influence understanding of leukemogensis as well as add to the understanding of the role stress response genes play in other cancers, and contribute to the development of new/improved modalities for treatment of cancer.