Metabolic basis of B cell lineage leukemia relapse

B细胞系白血病复发的代谢基础

基本信息

批准号：
10339722
负责人：
Markus Müschen
金额：
$ 100.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339722
关键词：
Acute Algorithms Autoimmune Diseases B-Lymphocytes B-cell precursor acute lymphoblastic leukemia cell Cell Death Cell Lineage Cells Child Clone Cells Diagnostic tests Disease Drug resistance Energy Metabolism FRAP1 gene Glucocorticoids Glycolysis Investigation Lesion Lymphoblastic Leukemia Medicine Metabolic Nature Oncogenic PAX5 gene Patient-Focused Outcomes Patients Pharmacology Pre-B Acute Lymphoblastic Leukemia Protein Tyrosine Kinase Relapse Resistance Risk SYK gene Signal Transduction Testing Toxic effect Treatment Protocols Work attenuation autoreactive B cell autoreactivity base cancer cell cell type chemotherapy exhaustion glucose metabolism glucose uptake high risk improved improved outcome inhibitor/antagonist innovation leukemia leukemia relapse pre-B cell receptor pre-clinical public health relevance response risk stratification transcription factor

项目摘要

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.

描述（由申请人提供）：意义：在过去的几十年里，B 期 ALL 患者的治疗结果已得到显着改善，然而，对于 15-20% 的儿童来说，在最初成功的治疗后，情况并非如此。根据风险分层，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 B ALL 复发前的患者将死于疾病，而其他患者则因不必要的毒性而遭受长期后遗症。该提议基于这样的中心观察：B 细胞系白血病的复发克隆对常规化疗具有抵抗力，但特别容易受到葡萄糖和能量代谢的干扰，因此，专门针对 B 细胞内在代谢倾向的药物可能会改善患有 B 细胞系白血病的患者的预后。原理和创新：与其他细胞类型不同，选择（前）B 细胞是为了从前 B 细胞发出中等水平的信号强度。细胞受体（前 BCR）：信号强度低于最小阈值（例如无功能的前 BCR）和过度激活（例如自身反应性前 BCR）都会触发阴性选择和细胞死亡。 ALL，包括复发性 ALL，受到与正常 B 细胞选择相同的规则的约束（Swaminathan 等人，Nature Medicine 2013）尽管存在致癌转化，但我们发现负选择的基本机制。我们小组最近的研究表明，前 BCR 酪氨酸激酶 SYK 的药理学过度激活会涉及删除检查点，这在功能上与自身反应性 B 细胞的阴性选择相同。我们发现，SYK 过度激活引起的细胞死亡是由 B 细胞谱系 ALL 细胞的急性能量消耗和糖酵解储备耗尽引起的。该提议基于对复发性克隆的集中观察。 B 细胞系白血病对传统化疗有抵抗力，但特别容易受到葡萄糖和能量代谢的干扰。假设：基于这些和其他发现，我们提议在未来七年内开发三个新的研究方向。在临床前环境中测试和完善这一治疗 B 系 ALL 复发的新兴概念 (1) 复发前 B ALL 细胞经常获得 B 细胞特异性转录因子 PAX5 的缺失，以及IKZF1，其功能意义尚不清楚，在此我们测试了以下假设：这些损伤降低了 B 细胞谱系定向的严格性，从而部分减轻了 B 细胞葡萄糖和能量代谢的内在负担 (2) 我们小组最近的研究表明。前 B ALL 细胞对 Syk-mTOR 信号传导的抑制性调节剂具有独特的依赖性（Shojaee 等人，Cancer Cell 2014；Chen 等人，Nature 2014）在此我们检验了信号传导抑制剂的假设。保护前 B ALL 细胞免受能量消耗和糖酵解储备耗尽，因此，参与删除检查点，这在功能上与自身反应性 B 细胞的负选择相同 (3) 糖皮质激素在杀死前 B 细胞方面非常有效。与任何其他细胞类型相比，B LL 细胞和自身反应性 B 细胞克隆对糖皮质激素的敏感性高出 75 倍以上。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，从而恶化 B 细胞固有的代谢负担。