Modeling ETP-ALL in mouse

描述(申请人提供)：早期T细胞前体急性淋巴细胞白血病(ETP-ALL)是一种新发现的白血病亚型，以前被认为是T细胞ALL(T-ALL)。这种儿童白血病与ETP干细胞有许多共同的特征，ETP干细胞保留了分化为T细胞和髓系的能力。与T-ALL相比，这种干细胞白血病的预后要差得多。目前，这种高度致命的儿童癌症还没有治疗方法，ETP-ALL白血病发生的分子机制仍不清楚。人类ETP-ALL的小鼠模型可能会加速对ETP-ALL发展过程中涉及的分子和细胞事件的剖析，并允许测试新的治疗方法。为此，我们发现，在给予苯并[a]芘(B[a]P)(一种与儿童ALL发展有关的环境致癌物质)后，PDLIM2基因敲除而不是野生型小鼠发展出所有与人类ETP-ALL非常相似的疾病。这些数据不仅揭示了这种含有PDZ-LIM结构域的蛋白在抑制ETP-ALL中的重要作用，而且也为人类ETP-ALL提供了第一线的动物模型。与小鼠的遗传学研究一致，我们的人类研究表明，抑制PDLIM2的表达是人类ETP-ALL发病的关键机制。基于这些创新的发现，我们将确定PDLIM2 KO小鼠的ETP-ALL是否与它们的人类同行具有共同的遗传和分子基础。我们将把这些研究的重点放在RAS基因激活突变的作用上，因为我们已经证明，PDLIM2 KO小鼠中的ETP-ALL存在RAS基因激活突变，这是B[a]P治疗的已知结果，也是人类ETP-ALL的标志。除了RAS突变，我们的初步研究还表明，在PDLIM2 KO小鼠或人类患者的ETP-ALL中，NF-B relA被结构性激活，重要的是，PDLIM2的重新表达抑制了人和小鼠ETP-ALL中RELA的致病激活。因此，我们还将确定RAS、RERA和PDLIM2在ETP-ALL发病机制中的作用和机制。这些研究将建立和表征一种新的ETP-ALL模型，并为ETP-ALL白血病的发生提供基础知识。这些研究还可能为这种高度致命但无法治愈的儿童白血病找到有效的治疗策略。

DESCRIPTION (provided by applicant): Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a newly identified subtype of leukemia that was previously considered and treated as T-cell ALL(T-ALL). This childhood leukemia shares many features in common with ETP stem-like cells, which retain the ability to differentiate into both T-cell and myeloid lineages. Compared to T-ALL, this stem cell leukemia has a much poorer prognosis. Currently, there is no treatment for this highly lethal pediatric cancer, and the molecular mechanisms underlying ETP-ALL leukemogenesis remain unknown. Mouse models of human ETP-ALL may expedite the dissection of the molecular and cellular events involved in the development of ETP-ALL, and allow the testing of novel therapeutic approaches. To this end, we have found that after administration of benzo[a]pyrene (B[a]P), an environmental carcinogen associated with the development of childhood ALL, PDLIM2 knockout but not wild-type mice develop ALL that closely resembles human ETP-ALL. These data not only reveal an essential role of this PDZ-LIM domain-containing protein in ETP-ALL suppression, but also provide the first line of animal models for human ETP-ALL. In line with the mouse genetic studies, our human studies suggest that repression of PDLIM2 expression is a key mechanism of human ETP-ALL pathogenesis. Based on these innovative findings, we will determine whether ETP-ALLs in PDLIM2 KO mice share a common genetic and molecular basis with their human counterparts. We will focus these studies on the role of activating mutations in Ras genes, since we have shown that ETP- ALLs in PDLIM2 KO mice harbor activating mutations in Ras genes, a known outcome of B[a]P treatment and a hallmark of human ETP-ALL. In addition to Ras mutations, our pilot studies also indicate that NF-¿B RelA is constitutively activated in ETP-ALLs in PDLIM2 KO mice or human patients, and importantly re-expression of PDLIM2 inhibits the pathogenic activation of RelA in both human and murine ETP-ALLs. Thus, we will also determine the role and mechanism by which Ras, RelA and PDLIM2 interact in ETP-ALL pathogenesis. These studies will establish and characterize a novel model of ETP-ALL, and provide fundamental knowledge on ETP-ALL leukemogenesis. These studies may also lead to effective therapeutic strategies for this highly lethal but incurable pediatric leukemia.