BCLW in lymphoma survival and resistance to targeted BCL2 family therapies

摘要 肿瘤发展的一个先决条件是获得对细胞凋亡的抵抗。这可以通过以下方式实现 多种机制，但人类癌症中经常发生的防止细胞凋亡的变化是 过表达一个或多个抗细胞凋亡的bcl2家族成员。BCL2本身经常 在多种类型的B细胞淋巴瘤和许多其他淋巴系和非淋巴系恶性肿瘤中过度表达。 由于癌细胞依赖bcl2生存，一种靶向的特异性bcl2抑制剂 已开发，ABT-199(Ventoclax)。尽管，万乃馨已被FDA批准用于治疗特定的 对于白血病，用万乃馨治疗BCL2水平高的B细胞淋巴瘤的临床试验并不成功， 如滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤(DLBCL) BCL2。结果表明，这些淋巴瘤不需要bcl2来继续生存，揭示了一种 在淋巴瘤使用什么来保护自己免受细胞凋亡的知识方面存在显著差距。最近，我们制作了 出乎意料的发现，BCLW，一个未被发现的抗细胞凋亡的BCL2家族成员 在精子发生中起重要作用，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BCLW水平较高的DLBCL患者有 在高级别滤泡性淋巴瘤中，bclw的表达高于bcl2。我们 也表明BCLW对于Burkitt淋巴瘤细胞的生存是必要的，并且BCLW水平增加 为Burkitt淋巴瘤细胞提供对三个抗凋亡bcl2家族靶向的抑制剂的耐药性 会员。因此，我们假设BCLW的过度表达是多种类型B细胞生存所必需的 细胞淋巴瘤，并使淋巴瘤细胞对万乃馨和其他bcl2家族抑制剂产生耐药性。我们 提出两个目的来检验这一假说。在目标1中，我们建议在多个方面评估BCLW的需求 不同类型B细胞淋巴瘤与bcl2家族其他成员的关系及其过度表达机制 在目标2中，我们建议确定bclw在抵抗抗凋亡bcl2抑制剂中的作用。 家庭成员和克服这种阻力的方法。这些目标的完成将大大增加 对bcl2蛋白家族的了解以及bclw在B细胞淋巴瘤中的作用和对 Bcl2家族成员的靶向抑制物。结果也可能导致淋巴瘤临床试验的改进， 以知识为基础的治疗组合的诊断、预后和治疗干预。

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.