BCLW in lymphoma survival and resistance to targeted BCL2 family therapies

总结 肿瘤发展的先决条件是获得对细胞凋亡的抗性。这可以通过以下方式实现： 多种机制，但在人类癌症中，保护细胞凋亡的一种常见改变是， 一种或多种抗凋亡BCL 2家族成员的过表达。BCL 2本身经常 在多种类型的B细胞淋巴瘤和许多其它淋巴和非淋巴恶性肿瘤中过表达。 由于认为癌细胞对BCL 2的生存依赖性，靶向特异性BCL 2抑制剂被用于治疗癌症。 开发，ABT-199（维奈托克）。虽然，维奈托克已被FDA批准用于治疗特定的 白血病，维奈托克的临床试验对于具有高水平BCL 2的B细胞淋巴瘤没有成功， 例如滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤（DLBCL BCL 2。结果表明，这些淋巴瘤不需要BCL 2来维持生存，揭示了一种新的免疫学机制。 淋巴瘤利用什么来保护自己免受细胞凋亡的知识存在重大差距。最近，我们 BCLW是一种未被研究的抗凋亡BCL 2家族成员， 在精子发生中很重要，在六种不同类型的B细胞淋巴瘤中过表达，包括 滤泡性淋巴瘤和DLBCL。我们确定了含有较高水平BCLW的DLBCL患者， BCLW在高级别滤泡性淋巴瘤中的表达高于BCL 2。我们 还表明BCLW对于Burkitt淋巴瘤细胞的存活是必需的， 为伯基特淋巴瘤细胞提供了对靶向三个抗凋亡BCL 2家族的抑制剂的抗性 成员因此，我们假设BCLW过表达对于多种类型的B细胞的存活是必要的。 细胞淋巴瘤，并赋予淋巴瘤细胞对维奈托克和其他BCL 2家族抑制剂的抗性。我们 我提出了两个目标来检验这个假设。在目标1中，我们建议以多种方式评估BCLW的要求 不同的B细胞淋巴瘤与其他BCL 2家族成员的关系及其过表达机制。 在目的2中，我们提出确定BCLW对抗凋亡BCL 2抑制剂的抗性的贡献。 家庭成员和克服这种阻力的方法。这些目标的实现将大大增加 了解BCL 2蛋白家族和BCLW对B细胞淋巴瘤的作用以及对 BCL 2家族成员的靶向抑制剂。结果也可能导致淋巴瘤临床试验的改进， 诊断学、免疫学和治疗干预与基于知识的治疗组合。

Summary A prerequisite for tumor development is acquiring resistance to apoptosis. This can be accomplished through multiple mechanisms, but a frequent alteration in human cancers that protects from apoptosis is the overexpression of one or more of the anti-apoptotic BCL2 family members. BCL2 itself is frequently overexpressed in multiple types of B cell lymphomas and many other lymphoid and non-lymphoid malignancies. Because of the perceived reliance of cancer cells on BCL2 for survival, a targeted specific BCL2 inhibitor was developed, ABT-199 (venetoclax). Although, venetoclax has been FDA approved for the treatment of specific leukemias, clinical trials with venetoclax have not been successful for B cell lymphomas with high levels of BCL2, such as follicular lymphomas and diffuse large B cell lymphomas (DLBCL) that have translocated or amplified BCL2. The results indicate these lymphomas do not require BCL2 for their continued survival, revealing a significant gap in knowledge of what lymphomas use to protect themselves from apoptosis. Recently, we made the unexpected discovery that BCLW, an unexplored anti-apoptotic BCL2 family member that was only thought to be important in spermatogenesis, was overexpressed in six different types of B cell lymphomas, including follicular lymphoma and DLBCL. We determined patients with DLBCL containing higher levels of BCLW had reduced survival, and BCLW was more highly expressed than BCL2 in higher grade follicular lymphoma. We also showed BCLW was necessary for the survival of Burkitt lymphoma cells, and increased levels of BCLW provided resistance to Burkitt lymphoma cells to an inhibitor that targets three anti-apoptotic BCL2 family members. Therefore, we hypothesize BCLW overexpression is necessary for the survival of multiple types of B cell lymphomas and confers resistance to lymphoma cells to venetoclax and other BCL2 family inhibitors. We propose two Aims to test this hypothesis. In Aim 1, we propose to evaluate the requirements of BCLW in multiple different B cell lymphomas in relationship to other BCL2 family members and mechanisms for its overexpression. In Aim 2, we propose to determine the contribution of BCLW to resistance to inhibitors of anti-apoptotic BCL2 family members and ways to overcome this resistance. Completion of these Aims will significantly increase knowledge into the BCL2 family of proteins and the contribution of BCLW to B cell lymphomas and resistance to targeted inhibitors of BCL2 family members. Results are also likely to lead to improved lymphoma clinical trials, diagnostics, prognostics, and therapeutic interventions with knowledge based treatment combinations.