Impact of primary tumor development stage on prognosis and outcome in B-ALL

描述（申请人提供）：b细胞急性淋巴细胞白血病（B-ALL）是儿童最常见的癌症。虽然B-ALL的治疗方法已经取得了很大进展，但仍有大约20%的患者对标准治疗没有反应。因此，加强我们对这些侵袭性B-ALL亚型背后的基本生物学理解的研究仍然很重要；因为这样的研究似乎可以为标准治疗失败的患者找到有效的治疗方法。目前的建议是基于观察到侵袭性B-ALL的特定亚型（“低次二倍体B-ALL”）可能来源于非常原始的b细胞前体。提出的前两个目标将验证这样的假设，即这些肿瘤不仅源于原始前体，而且还保留了这种细胞类型中表达的特定生物学途径的活性，特别是对来自前b细胞受体的信号的反应性。如果是这样，那么最近开发的用于成熟B细胞淋巴瘤（通常影响老年人）的药物可能适用于这一小部分B- all。因此，该提案的第三个目标是开发实验室方法来测试这些肿瘤是否对所讨论的药物类别（fostamatinib和ibrutinib）特别敏感。

DESCRIPTION (provided by applicant): B-cell Acute Lymphocytic Leukemia (B-ALL) is the most common cancer in children. While great progress has been made in the development of treatments for B-ALL, approximately 20% of patients still fail to respond to standard therapies. Thus, studies that enhance our understanding of the basic biology behind these aggressive sub-types of B-ALL remain important; as such research could plausibly identify effective therapies for patients who have failed standard treatment. The present proposal is based on the observation that a specific sub-type of aggressive B-ALL ("low hypodiploid B-ALL") may be derived from very primitive precursors of B-cells. The first two aims proposed will test the hypothesis that these tumors not only derive from primitive precursors, but also retain the activity of specific biological pathways expressed in this cell type, specifically responsiveness t signals from the pre-B cell receptor. If so, then drugs recently developed for mature B cell lymphomas (which typically affect the elderly) may be applicable in this small subset of B-ALL. Thus, the third aim of the proposal is to develop laboratory methods by which to test whether these tumors are especially sensitive to the drug class in question (fostamatinib and ibrutinib).