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

描述（由申请方提供）：尽管在确定与儿童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显著进展，但为什么约20%的患者患有侵袭性疾病、对治疗反应差以及与生存期差相关尚不清楚。本申请的显著特点是从发展的角度来处理这一问题。我们认为，除了特殊的染色体易位，B细胞谱系也发挥了突出的作用，在B-ALL的进展。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，但存在第二个B-1细胞群体，其来源于B-1祖细胞，其在胎儿中的产生最稳健。由于B-1祖细胞是高度增殖的细胞，凋亡率低，我们假设一些儿童B-ALL是B-1恶性肿瘤，这些表现出积极的临床过程。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迅速发展为B-ALL。目标1中的实验将通过从TEL-AML 1 x Cdkn 2a-/-小鼠和BCR-ABL转基因小鼠收获B-1和B-2祖细胞来证实和扩展该观察结果，TEL-AML 1 x Cdkn 2a-/-小鼠在中位7个月大时发生B-ALL，BCR-ABL转基因小鼠在出生后数周内死于侵袭性B-ALL。这些实验将提供一个生物学证明，B细胞谱系可以是一个主要因素，决定淋巴细胞白血病的进展。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发生的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反映在Aim 1中产生的B-1与B-2白血病中。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形式的B-ALL中复制。最后，我们将确定是否识别的签名， 侵袭性鼠肿瘤具有作为具有相似特征的人B-ALL亚型的早期检测标记的转化潜力。我们的提案的结果是为了回应PA-08-267而提交的，它将为为什么某些形式的B-ALL特别具有攻击性提供新的生物学见解。此外，这项工作有可能选择一组可靠的生物标志物用于ALL的风险评估。

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.