Metabolic gatekeepers in B-cell malignancies

摘要 在B细胞受体（BCR）或其致癌基因下游引入激酶的小分子抑制剂， 模拟B细胞恶性肿瘤患者的显著改善的结果。然而，用激酶治疗- 单独的抑制剂总是选择耐药克隆。后续复发的发展仍然是一个 治疗B-ALL、CLL和套细胞淋巴瘤（MCL）患者的中心问题， 结果不佳或仍然是不治之症。 在过去的五年里，我们的R35支持的研究为B细胞肿瘤的治疗带来了新的范式： 与其他类型的癌症不同，B细胞恶性肿瘤对靶向参与负性肿瘤非常敏感。 选择，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，负选择机制不仅在预防自身免疫性疾病中起作用， 疾病，而且还代表了B细胞恶性肿瘤中的一类全新的治疗靶点。主要动力 现在，该更新申请的一个重要目的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。 这些方法之一是基于BCR下游激酶的药理学超活化，以模拟 自身反应性BCR的过度信号强度。传统上，靶向癌症治疗的重点是 激酶抑制剂来抑制致癌信号。我们的激酶超活化概念有效地代表了 相反 我们追求新的范式，即负选择是基于B淋巴转录程序， 限制能量丰富，我们称之为“代谢守门人”的机制。鉴于转化的B细胞具有 更高的能量需求比他们正常的同行，我们假设，代谢看门人机制 限制能量供应将通过设置低阈值来消除癌前病变来防止B细胞转化。 基于能量压力的克隆。 我们的实验室最近开发了遗传系统，以确定决定B独特形态的因素- 细胞，即B细胞具有比任何其他体细胞类型更小的细胞大小和更少的线粒体。我们 研究小细胞大小的维持如何影响B细胞选择以及B细胞如何被工程化以诱导 增大细胞大小和线粒体质量变得更易于恶性转化。 对单个B细胞淋巴瘤细胞的长期生物量测量揭示了周期性的萎缩阶段 （静止，BCL 6+）和扩增（增殖，MYC+）细胞团。我们将研究新的范式， BCL 6和MYC标志着休眠和激活的反复循环。与睡眠-觉醒阶段类似，我们 假设静止的BCL 6相对于恢复和再生是必不可少的。这些和其他 观察将导致新的概念，了解细胞大小和恢复期的长度 调节能量供应和转化B细胞的存活，并为治疗创造新的机会。 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.