Metabolic gatekeepers in B-cell malignancies

摘要 B细胞受体(BCR)或其致癌基因下游小分子激酶抑制剂的引入 模拟显著改善B细胞恶性肿瘤患者的预后。然而，用激酶治疗- 只有抑制剂才能选择抗药性克隆。随后复发的发展仍然是一个 B-ALL、CLL和套细胞淋巴瘤(MCL)患者治疗中的中心问题 结果不佳或仍是不治之症。 在过去的五年里，我们的R35支持的研究带来了治疗B细胞肿瘤的新范式： 与其他癌症类型不同，B细胞恶性肿瘤非常容易受到靶向负性接触的影响 选择，一种B细胞的内在机制，以防止有害的自身抗体和自身免疫性疾病。 与既定的教条相反，负选择的机制不仅在预防自身免疫方面是积极的 它不仅代表了一种全新的B细胞恶性肿瘤的治疗靶点。主要推动力 这一更新应用的关键是利用这些新概念来开发治疗策略 这将克服B-ALL、CLL和MCL的传统耐药机制。 其中一种方法是基于药物对bcr下游激酶的过度激活来模拟 来自自动反应BCR的过度信号强度。传统上，靶向癌症治疗的重点是 抑制致癌信号的激酶抑制剂。我们的激酶过度激活的概念有效地代表了 恰恰相反。 我们追求一种新的范式，即否定选择是基于B淋巴样转录程序来实现的 限制能量丰度，我们称之为“新陈代谢看门人”的机制。鉴于转化后的B细胞 更高的能量需求，我们假设新陈代谢守门人机制 限制能量供应将通过设定低门槛消除癌前病变来防止B细胞转化 基于能量压力的克隆。 我们实验室最近开发了遗传系统来识别决定B-B细胞独特形态的因素 细胞，即B细胞比任何其他体细胞类型具有更小的细胞尺寸和更少的线粒体。我们 研究维持小细胞大小如何影响B细胞选择，以及B细胞如何被工程诱导 细胞体积增大，线粒体质量变得更容易恶变。 单个B细胞淋巴瘤细胞的长期生物量测量显示出周期性的萎缩阶段 (静止期，BCL6+)和扩张期(增殖期，MYC+)细胞团。我们将研究新的范式， Bcl6和MYC标志着休眠和激活的迭代周期。在类似于睡眠-觉醒阶段，我们 假设静止的BCL6相对于恢复和再生是必不可少的。这些和其他 观察将导致对细胞大小和恢复期长度的理解的新概念 调节转化B细胞的能量供应和存活，为治疗创造新的机遇 B细胞恶性肿瘤的干预，重点是B-ALL、CLL和MCL。

ABSTRACT The introduction of small molecule inhibitors of kinases downstream of the B-cell receptor (BCR) or its oncogenic mimics substantially improved outcomes for patients with B-cell malignancies. However, treatment with kinase- inhibitors alone invariably selects for drug-resistant clones. The development of subsequent relapse remains a central problem in the treatment of patients with B-ALL, CLL and mantle cell lymphoma (MCL), which continue to have poor outcomes or remain incurable diseases. Over the past five years, our R35-supported research led to a new paradigm for the treatment of B-cell tumors: Unlike other cancer-types, B-cell malignancies are highly susceptible to targeted engagement of negative selection, a B-cell-intrinsic mechanism to protect against harmful autoantibodies and autoimmune disease. Contrary to established dogma, mechanisms of negative selection are not only active in preventing autoimmune disease but also represent an entirely novel class of therapeutic targets in B-cell malignancies. The main impetus of this renewal application is now to leverage these new concepts for the development of treatment strategies that will overcome conventional mechanisms of drug-resistance in B-ALL, CLL and MCL. One of these approaches is based on pharmacological hyperactivation of BCR-downstream kinases to mimic excessive signaling-strength from an autoreactive BCR. Targeted cancer-therapy is traditionally focused on kinase-inhibitors to suppress oncogenic signaling. Our concept of kinase-hyperactivation effectively represents the opposite. We pursue the new paradigm that negative selection is predicated on a B-lymphoid transcriptional program to restrict energy-abundance, a mechanism we termed `metabolic gatekeeper'. Given that transformed B-cells have higher energy-demands than their normal counterparts, we hypothesize that metabolic gatekeeper mechanisms to limit energy-supply will prevent B-cell transformation by setting low thresholds for elimination of pre-malignant clones based on energy-stress. Our laboratory recently developed genetic systems to identify factors that dictate the unique morphology of B- cells, i.e. that B-cells have a smaller cell size and fewer mitochondria than any other somatic cell type. We examine how maintenance of a small cell-size affects B-cell selection and how B-cells engineered to inducibly increase cell size and mitochondrial mass become more prone to malignant transformation. Long-term biomass-measurements of single B-cell lymphoma cells revealed periodic phases of shrinking (quiescence, BCL6+) and expanding (proliferation, MYC+) cell mass. We will examine the new paradigm that BCL6 and MYC mark iterative cycles of dormancy and activation. In analogy to sleep-wake phases, we hypothesize that the quiescent BCL6-phase is essential for recovery and regeneration. These and other observations will lead to new concepts for the understanding of how cell-size and the length of recovery-periods regulate energy-supply and survival of transformed B-cells and create new opportunities for therapeutic intervention in B-cell malignancies with a focus on B-ALL, CLL and MCL.