Impact of B-Cell Lineage on Progression of B-Acute Lymphoblastic Leukemia

B 细胞谱系对 B 急性淋巴细胞白血病进展的影响

• 批准号: 8427254
• 负责人: KENNETH Allan DORSHKIND
• 金额: $ 18.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427254
• 关键词: Acute Lymphocytic Leukemia; Address; Affect; Age-Months; Aggressive Clinical Course; Aggressive course; Apoptosis; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Biological; Biological Markers; Biology; Birth; Bone Marrow; Cell Lineage; Cells; Characteristics; Childhood; Chromosomal translocation; Clinical; Collaborations; Data; Development; Disease; ETV6 gene; Early Diagnosis; Exhibits; Fetus; Future; Gene Expression Profile; Genes; Genetic; Genetically Engineered Mouse; Harvest; Hematopoietic; Human; Immune response; Institution; Investigation; Lymphoblastic Leukemia; MLLT2 gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediator of activation protein; Microarray Analysis; Molecular Abnormality; Mus; Patients; Play; Population; Production; RUNX1 gene; Risk Assessment; Role; Testing; Time; Transgenes; Transgenic Mice; Treatment Protocols; Work; adaptive immunity; base; bcr-abl Fusion Proteins; expectation; fetal; in utero; insight; leukemia; mouse model; progenitor; prognostic; public health relevance; research study; response; tool; tumor

DESCRIPTION (provided by applicant): Despite significant advances in identifying distinct chromosomal translocations associated with pediatric B- Acute Lymphoblastic Leukemia (B-ALL), why ~20% of patients present with disease that is aggressive, responds poorly to therapy, and is associated with poor survival is unknown. The distinguishing feature of this application is the developmental perspective from which this question is addressed. We propose that in addition to the particular chromosomal translocation, B cell lineage also plays a prominent role in B-ALL progression. While most B cells are generated from B-2 progenitors produced in post-natal bone marrow, a second population of B-1 cells that derive from B-1 progenitors whose production is most robust in the fetus exists. Because B-1 progenitors are highly proliferative cells with low rates of apoptosis, we hypothesize that some childhood B-ALLs are B-1 malignancies and that these exhibit an aggressive clinical course. In an initial, proof of concept experiment, we observed that BCR-ABL transduced B-1 progenitors developed a rapid B-ALL in recipient mice. Experiments in Aim 1 will confirm and extend this observation by harvesting B-1 and B-2 progenitors from TEL -AML1 x Cdkn2a-/- mice, which develop B-ALL at a median of seven months of age, and BCR-ABL transgenic mice, which succumb to an aggressive B-ALL within weeks after birth. These experiments will provide a biological demonstration that B-cell lineage can be a major factor that determines the progression of lymphoblastic leukemia. Studies in Aim 2 will determine if the gene signature of normal B-1 and B-2 progenitors is reflected in the biology of the B-ALL that develops. We will isolate normal B-1 and B-2 progenitors and analyze patterns of gene expression in them using microarray analysis. We will then determine how these signatures are reflected in the B-1 versus B-2 leukemias generated in Aim 1. The expectation is that the genetic network that correlates with the high rate of proliferation and low levels of apoptosis exhibited by normal B-1 progenitors will also be duplicated in aggressive forms of B-ALL. Finally, we will determine if the signatures identified in the aggressive murine tumors have translational potential as early detection markers of sub-types of human B-ALL with similar characteristics. The results of our proposal, which is being submitted in response to PA-08-267, will provide new biological insights into why some forms of B-ALL are particularly aggressive. Moreover, the work has the potential to select a robust set of biomarkers for risk assessment in ALL.

描述（由申请人提供）：尽管在识别与儿童 B 急性淋巴细胞白血病 (B-ALL) 相关的不同染色体易位方面取得了重大进展，但为什么约 20% 的患者会出现侵袭性、对治疗反应不佳且与生存率低相关的疾病。该应用程序的显着特征是解决该问题的发展视角。我们认为，除了特定的染色体易位之外，B 细胞谱系也在 B-ALL 进展中发挥着重要作用。虽然大多数 B 细胞是由出生后骨髓中产生的 B-2 祖细胞产生的，但存在源自 B-1 祖细胞的第二群 B-1 细胞，其产生在胎儿中最为强劲。由于 B-1 祖细胞是高度增殖的细胞，凋亡率低，因此我们假设一些儿童 B-ALL 是 B-1 恶性肿瘤，并且表现出侵袭性的临床病程。在最初的概念验证实验中，我们观察到 BCR-ABL 转导的 B-1 祖细胞在受体小鼠中快速形成 B-ALL。目标 1 中的实验将通过从 TEL -AML1 x Cdkn2a-/- 小鼠和 BCR-ABL 转基因小鼠中收获 B-1 和 B-2 祖细胞来证实和扩展这一观察结果，TEL -AML1 x Cdkn2a-/- 小鼠在平均 7 个月大时发生 B-ALL，而 BCR-ABL 转基因小鼠则在出生后几周内死于侵袭性 B-ALL。这些实验将提供生物学证明，证明 B 细胞谱系可能是决定淋巴细胞白血病进展的主要因素。目标 2 中的研究将确定正常 B-1 和 B-2 祖细胞的基因特征是否反映在所形成的 B-ALL 的生物学中。我们将分离正常的 B-1 和 B-2 祖细胞，并使用微阵列分析来分析它们的基因表达模式。然后，我们将确定这些特征如何在目标 1 中产生的 B-1 与 B-2 白血病中得到反映。预期与正常 B-1 祖细胞表现出的高增殖率和低水平凋亡相关的遗传网络也将在侵袭性 B-ALL 中复制。最后，我们将确定中识别的签名是否 侵袭性小鼠肿瘤具有转化潜力，可作为具有相似特征的人类 B-ALL 亚型的早期检测标志物。我们针对 PA-08-267 提交的提案结果将为解释为什么某些形式的 B-ALL 具有特别的侵袭性提供新的生物学见解。此外，这项工作有可能选择一组强大的生物标志物用于 ALL 的风险评估。