Role of NF-kB Activity in Muyltiple Myeloma

描述(申请人提供)：核因子-kB(核因子-kB)是一种转录因子，不仅促进衰老过程本身，而且被认为在许多与衰老有关的疾病的发展和致病中发挥不可或缺的作用，包括癌症。特别是，核因子-kB与多发性骨髓瘤(MM)有关，MM是一种在老年患者中异常常见的血液恶性肿瘤，其特征是骨髓中血浆B细胞的克隆性增殖。这种疾病80%的患者年龄都在60岁以上。尽管最近在化疗和移植治疗方面取得了进展，但MM的中位生存期只有三年。因此，治疗的进步将需要对这种疾病的生物学有更好的了解。原代骨髓瘤细胞具有活性的核因子-kB，这似乎是肿瘤生存的关键。核因子-kB也在肿瘤细胞与其支持的微环境，包括骨髓基质细胞(BMSCs)之间的相互作用中发挥作用。蛋白酶体抑制剂Bortezomib被认为至少部分是通过抑制NF-kB活性起作用的，最近被批准用于治疗MM。虽然该药物在临床上取得了相对成功，但对Bortezomib的初始和发展耐药是常见的。Bortezomib的确切分子机制以及那些介导耐药的分子机制尚不完全清楚。我们的初步研究表明，大多数原发患者和多发性骨髓瘤细胞系中的结构性核因子-kB对硼替佐米治疗具有耐药性。我们还观察到，MM细胞与来自MM患者的BMSCs(而不是来自非MM患者的BMSCs)共培养，进一步激活了这些细胞中的NF-kB，这种增强的活性也大多对Bortezomib治疗耐药。通过突变和生化分析，本研究探讨了MM细胞中耐药的核因子-kB活性的分子机制。这项建议的具体目标是描述IkBA作为Bortezomib耐药降解底物所需的顺式元件，并在MM中寻找新的耐Bortezomib核因子-kB上游激活剂。这些研究将有助于更好地了解与年龄相关的恶性MM的毒力，并改善受这种疾病影响的老年患者的健康和福祉。相关：核因子-kB是一种蛋白质，可以帮助肿瘤细胞存活并抵御化疗。通过了解核因子-kB的调节，我们可能能够更好地预测患者是否对化疗有反应，并发现新药。这将有助于避免患者遭受这些药物不必要的副作用。

DESCRIPTION (provided by applicant): Nuclear Factor-kappa B (NF-kB) is a transcription factor that not only contributes to the aging process itself, but is believed to play an integral role in the development and pathogenicity of many diseases associated with aging, including cancer. In particular, NF-kB is implicated in multiple myeloma (MM), a hematologic malignancy that is exceptionally common in older patients and is characterized by the clonal expansion of plasma B cells in the bone marrow. 80% of patients with this disease are over 60 years old. Despite recent advances in chemo and transplant therapy, MM has a median survival of only three years. Thus, advancement of therapy will require a better understanding of the biology of this disease. Primary myeloma cells possess active NF-kB, which appears to be crucial for tumor survival. NF-kB also plays a role in the interactions between tumor cells and their supporting microenvironment, including bone marrow stromal cells (BMSCs). The proteasome inhibitor bortezomib is believed to work at least in part through the inhibition of NF-kB activity, and was recently approved for the treatment of MM. While this drug has had relative success in the clinic, initial and developed resistance to bortezomib are common occurrences. The exact molecular mechanisms of bortezomib and those that mediate resistance to the drug are not completely understood. Our preliminary studies suggest that constitutive NF-kB in the majority of both primary patient and MM cell lines is resistant to bortezomib treatment. We also observe that co- culture of MM cells with BMSCs derived from MM patients, and not those derived from non-MM patients, further activates NF-kB in these cells, and that this enhanced activity is also mostly resistant to bortezomib treatment. Through mutational and biochemical analysis, this proposal addresses the molecular mechanisms of bortezomib resistant NF-kB activity in MM cells. The specific goals of this proposal are to delineate the cis-elements of IkBa that are required for it to be a substrate of bortezomib-resistant degradation, and to identify novel upstream activators of bortezomib-resistant NF-kB in MM. These studies will help to better understand the virulence of the age-associated malignancy, MM, and to improve the health and well-being of older patients affected by this disease. Relevance: NF-kB is a protein that can help tumor cells survive and defend themselves against chemotherapy. By understanding the regulation of NF-kB, we may be able to better predict if a patient will respond to chemotherapies, and to discover new drugs. This will help avoid subjecting patients to the side effects of these drugs unnecessarily.