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

基本信息

批准号：
8606446
负责人：
KENNETH Allan DORSHKIND
金额：
$ 19.72万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606446
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

项目摘要

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）：尽管在识别与儿科B-急性淋巴细胞白血病（B-all）相关的明显染色体易位方面取得了重大进展，为什么约有20％的患者患有侵略性的疾病，对治疗反应良好，并且与不良生存有关。该应用程序的区别特征是从中解决了这个问题的发展观点。我们建议，除了特定的染色体易位外，B细胞谱系还在B-all进展中起着重要作用。虽然大多数B细胞是由产后骨髓中产生的B-2祖细胞产生的，但源自B-1祖细胞的第二个B-1细胞群，其产生在胎儿中最强大。由于B-1祖细胞是高度凋亡率较低的高度增殖细胞，因此我们假设某些童年B-ALLS是B-1恶性肿瘤，并且表现出侵略性的临床过程。在最初的概念证明实验中，我们观察到BCR-ABL转导的B-1祖细胞在受体小鼠中发展了B-All快速。 AIM 1中的实验将通过从Tel -AML1 X CDKN2A - / - 小鼠中收集B-1和B-2祖细胞来确认和扩展该观察结果，这些祖细胞在七个月大的七个月大的中位数和BCR-ABL转基因小鼠中形成B-all，而BCR-ABL转基因小鼠在出生后几周内屈服于积极的B-all。这些实验将提供一个生物学证明，即B细胞谱系可能是决定淋巴细胞白血病进展的主要因素。 AIM 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出现的B-All的生物学中。我们将使用微阵列分析分析正常的B-1和B-2祖细胞，并分析其基因表达模式。然后，我们将确定在AIM 1中产生的B-1与B-2白血病中如何反映这些特征。期望是，与正常B-1祖细胞所表现出的高水平凋亡率相关的遗传网络也将以B-B-all的侵略性形式重复。最后，我们将确定是否在侵略性鼠肿瘤具有转化的潜力，作为具有相似特征的人类B-All的子类型的早期检测标志物。我们的提案结果是根据PA-08-267提交的，它将提供新的生物学见解，以了解为什么某些形式的B-All特别具有侵略性。此外，这项工作有可能选择一组强大的生物标志物进行风险评估。