Metabolic basis of B cell lineage leukemia relapse

 描述(由申请人提供)：意义：在过去的几十年里，前B组患者的结果都有了实质性的改善。然而，15%-20%的儿童在最初成功的治疗后复发，情况并非如此。在目前的风险分层算法下，这些患者与标准化疗反应良好的患者无法区分。因此，大多数前B期ALL复发的患者将死于他们的疾病，而其他人则因不必要的毒性而遭受长期后遗症。这一建议是基于中心观察，即B细胞系白血病中的复发克隆对常规化疗具有耐药性，但特别容易受到葡萄糖和能量代谢干扰的影响。因此，针对B细胞固有代谢易感性的药物可能会改善复发白血病患者的预后，而不会增加治疗方案的实质性毒性。原理和创新：与其他细胞类型不同，(前)B细胞被选为中等水平的信号强度。关键的生存和增殖信号来自前B细胞受体(Pre-BCR)：信号强度低于最小值(例如，无功能的Pre-BCR)和高于最大值(例如，自身反应性Pre-BCR)阈值的过度激活都会触发负选择和细胞死亡。我们最近发现，Pre-B ALL，包括复发ALL，受到同样管理正常B细胞选择的相同规则的约束(Swminathan等人，自然医学，2013)。尽管有致癌转化，但我们发现负选择的基本机制在Pre-B ALL中仍然起作用。本课题组最近的研究表明，bcr前酪氨酸激酶SYK的药物过度激活涉及一个缺失检查点，这在功能上等同于自身反应性B细胞的阴性选择。在对这一提议的初步研究中，我们发现SYK过度激活导致的细胞死亡是由于B细胞系ALL细胞的急性能量耗竭和糖酵解储备耗尽所致。这一建议是基于中心观察，即B细胞系白血病中的复发克隆对常规化疗具有耐药性，但特别容易受到葡萄糖和能量代谢干扰的影响。假设：基于这些和其他发现，我们提出了三条新的调查路线，将在未来七年内开发。这将使我们能够在临床前环境中测试和改进这一治疗B系ALL复发的新兴概念。(1)复发性Pre-B ALL细胞经常发生B细胞特异性转录因子PAX5和IKZF1的缺失，其功能意义尚不清楚。在这里，我们测试的假设是，这些病变降低了B细胞谱系承诺的严格性，从而在一定程度上减轻了B细胞固有的葡萄糖和能量代谢负担。(2)我们团队最近的研究显示，Pre-B ALL细胞对Syk-mTOR信号的抑制调节剂特别上瘾(Shojaee等人，癌症细胞2014；Chen等人，自然2014)。在这里，我们测试了一种假设，即信号抑制剂保护前B细胞免受能量耗竭和糖酵解储备的耗尽，从而参与缺失检查点，这在功能上等同于对自身反应性B细胞的阴性选择。(3)糖皮质激素对自身免疫性疾病中的前B细胞和自身反应性B细胞克隆均有高效杀伤作用。与任何其他类型的细胞相比，B细胞系细胞对糖皮质激素的敏感性高出75倍。在这里，我们假设糖皮质激素通过抑制葡萄糖摄取和糖酵解，导致急性能量耗竭，从而加剧B细胞固有的代谢责任。

 DESCRIPTION (provided by applicant): Significance: Outcomes for patients with pre-B ALL have substantially improved over the past decades. However, this is not the case for 15-20% of children who relapse after initially successful treatment. With current algorithms of risk stratification, these patients are undistinguishable from patients who respond well to standard chemotherapy. As a consequence, most patients with pre-B ALL relapse will die from their disease, while others suffer long-term sequelae from unnecessary toxicity. This proposal is based on the central observation that relapse clones in B cell lineage leukemia are resistant to conventional chemotherapy but uniquely vulnerable to perturbations of glucose and energy metabolism. Therefore, agents that specifically target B cell-intrinsic metabolic liabilities may improve outcomes for patients with relapse leukemia without adding substantive toxicity to the treatment regimen. Rationale and Innovation: Unlike other cell types, (pre-) B cells are selected for an intermediate level signaling strength. Critical survival and proliferation signals emanate from the pre-B cell receptor (pre-BCR): Both attenuation below minimum (e.g. non-functional pre-BCR) and hyperactivation above maximum (e.g. autoreactive pre-BCR) thresholds of signaling strength trigger negative selection and cell death. We recently discovered that pre-B ALL, including relapse ALL, is bound by the same rules that also govern normal B cell selection (Swaminathan et al., Nature Medicine 2013). Despite oncogenic transformation, we found that basic mechanisms of negative selection are still functional in pre-B ALL. Recent studies by our group demonstrated that pharmacological hyperactivation of the pre-BCR tyrosine kinase SYK engages a deletional checkpoint, which is functionally equivalent with negative selection of autoreactive B cells. In preliminary studies for this proposal, we found that cell death in response to SYK hyperactivation is caused by acute energy depletion and exhaustion of glycolytic reserves of B cell lineage ALL cells. This proposal is based on the central observation that relapse clones in B cell lineage leukemia are resistant to conventional chemotherapy but uniquely vulnerable to perturbations of glucose and energy metabolism. Hypotheses: Based on these and other findings, we are proposing three new lines of investigation to be developed over the next seven years. This will allow us to test and refine this emerging concept for the treatment of B-lineage ALL relapse in a pre-clinical setting. (1) Relapse pre-B ALL cells frequently acquire deletions of B cell-specific transcription factors PAX5, and IKZF1, the functional significance of which is not known. Here we test the hypothesis that these lesions reduce stringency of B cell lineage commitment and thereby in part mitigate B cell intrinsic liabilities of glucose and energy metabolism. (2) Recent studies by our group revealed that pre-B ALL cells are uniquely addicted to inhibitory regulators of Syk-mTOR signaling (Shojaee et al., Cancer Cell 2014; Chen et al., Nature 2014). Here we test the hypothesis that signaling inhibitors protect pre-B ALL cells from energy depletion and exhaustion of glycolytic reserves and, hence, engagement of a deletional checkpoint, that is functionally equivalent with negative selection of self-reactive B cells. (3) Glucocorticoids are highly effective in killing both pre-B LL cells and self-reactive B cell clones in autoimmune diseases. Compared to any other cell types, B cell lineage cells are >75-fold more sensitive to glucocorticoids. Here we hypothesize that glucocorticoids, by inhibiting glucose uptake and glycolysis, cause acute energy depletion and, hence, exacerbate B cell-intrinsic metabolic liabilities.