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

描述(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%的患者患有侵袭性疾病，对治疗反应差，并与低存活率相关，目前尚不清楚。这一应用程序的显著特点是从发展的角度来解决这个问题。我们认为，除了特殊的染色体易位外，B细胞系在B-ALL的进展中也起着重要的作用。虽然大多数B细胞是从出生后骨髓中产生的B-2祖细胞产生的，但也存在第二批B-1细胞，它们来自B-1祖细胞，其产生在胎儿中最健壮。因为B-1祖细胞是高增殖低凋亡率的细胞，我们假设一些儿童B-ALL是B-1恶性肿瘤，并表现出侵袭性的临床过程。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发展迅速的B-ALL。AIM 1的实验将证实并扩大这一观察结果，方法是从TEL-AML1x CDKN2a-/-小鼠和BCR-ABL转基因小鼠身上采集B-1和B-2祖细胞，这些小鼠在出生后的中位数7个月内都会出现B-ALL，而BCR-ABL转基因小鼠在出生后几周内都会死于攻击性的B-。这些实验将提供一个生物学证据，证明B细胞谱系可能是决定淋巴母细胞白血病进展的主要因素。目标2的研究将确定正常的B-1和B-2祖细胞的基因签名是否反映在发育的B-ALL的生物学中。我们将分离正常的B-1和B-2祖细胞，并利用基因芯片分析它们的基因表达模式。然后我们将确定这些信号如何反映在AIM 1产生的B-1和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，我们将确定在 侵袭性小鼠肿瘤具有作为人类B亚型早期检测标记的翻译潜力-所有这些亚型都具有相似的特征。我们针对PA-08-267提交的提案的结果将为为什么某些形式的B-ALL特别具有侵略性提供新的生物学见解。此外，这项工作有可能选择一套可靠的生物标记物进行总体风险评估。

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.