Metabolic basis of B cell lineage leukemia relapse

 描述（由申请人提供）：意义：在过去的几十年中，前B ALL患者的结局得到了实质性改善。然而，15-20%的儿童在最初成功治疗后复发的情况并非如此。根据目前的风险分层算法，这些患者与对标准化疗反应良好的患者无法区分。因此，大多数前B ALL复发患者将死于疾病，而其他患者则因不必要的毒性而遭受长期后遗症。这个建议是基于中心的观察，复发克隆在B细胞系白血病是耐药的常规化疗，但特别容易受到干扰的葡萄糖和能量代谢。因此，特异性靶向B细胞内在代谢倾向的药物可能会改善复发性白血病患者的预后，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细胞被选择用于中等水平的信号强度。关键的存活和增殖信号来自前B细胞受体（前BCR）：信号强度的最小值以下的衰减（例如无功能的前BCR）和最大值以上的超活化（例如自身反应性前BCR）都会触发负选择和细胞死亡。我们最近发现前B ALL，包括复发ALL，受同样支配正常B细胞选择的规则约束（Swaminathan et al.，Nature Medicine 2013）。尽管有致癌性转化，我们发现负选择的基本机制在前B ALL中仍然起作用。我们小组最近的研究表明，前BCR酪氨酸激酶SYK的药理学超活化涉及缺失检查点，其功能与自身反应性B细胞的阴性选择等同。在对这一提议的初步研究中，我们发现响应于SYK超活化的细胞死亡是由急性能量消耗和B细胞系ALL细胞的糖酵解储备耗尽引起的。这个建议是基于中心的观察，复发克隆在B细胞系白血病是耐药的常规化疗，但特别容易受到干扰的葡萄糖和能量代谢。假设：基于这些和其他发现，我们提出了三个新的调查线，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完善这一新兴概念，用于治疗B系ALL复发。(1)复发前B ALL细胞经常获得B细胞特异性转录因子PAX 5和IKZF 1的缺失，其功能意义尚不清楚。在这里，我们测试的假设，这些病变减少严格的B细胞谱系的承诺，从而在一定程度上减轻B细胞的内在负债的葡萄糖和能量代谢。(2)我们小组最近的研究揭示了前B ALL细胞独特地对Syk-mTOR信号传导的抑制性调节剂成瘾（Shojaee等人，Cancer Cell 2014; Chen等人，Nature 2014）。在这里，我们测试的假设，信号传导抑制剂保护前B ALL细胞的能量消耗和糖酵解储备耗尽，因此，参与删除检查点，这是功能上等同于自我反应性B细胞的负选择。(3)糖皮质激素在杀死自身免疫性疾病中的前B LL细胞和自身反应性B细胞克隆中是高度有效的。与任何其他细胞类型相比，B细胞谱系细胞对糖皮质激素的敏感性高75倍以上。 在此，我们假设糖皮质激素通过抑制葡萄糖摄取和糖酵解，导致急性能量消耗，从而加剧B细胞固有的代谢负债。

 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.