Modeling ETP-ALL in mouse

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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.