Role of NF-kB Activity in Muyltiple Myeloma

描述（由申请人提供）：核因子κ B （NF-kB）是一种转录因子，不仅有助于衰老过程本身，而且被认为在包括癌症在内的许多与衰老相关的疾病的发展和致病性中起着不可或缺的作用。特别是，NF-kB与多发性骨髓瘤（MM）有关，这是一种在老年患者中特别常见的血液恶性肿瘤，其特征是骨髓中浆B细胞的克隆扩增。80%的患者年龄在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的中位生存期仅为3年。因此，治疗的进步将需要更好地了解这种疾病的生物学。原发性骨髓瘤细胞具有活性NF-kB，这似乎对肿瘤的生存至关重要。NF-kB还在肿瘤细胞及其支持微环境（包括骨髓基质细胞）之间的相互作用中发挥作用。蛋白酶体抑制剂硼替佐米被认为至少部分通过抑制NF-kB活性起作用，最近被批准用于治疗MM。虽然该药物在临床中取得了相对成功，但对硼替佐米的初始和发展耐药性是常见的。硼替佐米的确切分子机制和介导药物耐药性的分子机制尚不完全清楚。我们的初步研究表明，大多数原发性患者和MM细胞系中的组成型NF-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患者的骨髓间充质干细胞共同培养，而不是来自非MM患者的骨髓间充质干细胞，进一步激活了这些细胞中的NF-kB，并且这种增强的活性也大多对硼替佐米治疗具有抗性。通过突变和生化分析，本文探讨了MM细胞中硼替佐米耐药NF-kB活性的分子机制。该提案的具体目标是描述IkBa的顺式元件，这些元件是使其成为耐硼替佐米降解的底物所必需的，并确定MM中耐硼替佐米NF-kB的新型上游激活剂。这些研究将有助于更好地了解年龄相关恶性肿瘤MM的毒性，并改善受该疾病影响的老年患者的健康和福祉。相关性：NF-kB是一种可以帮助肿瘤细胞存活并抵御化疗的蛋白质。通过了解NF-kB的调控，我们可能能够更好地预测患者是否对化疗有反应，并发现新的药物。这将有助于避免患者不必要地遭受这些药物的副作用。

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.