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.
The proposed investigations will characterize and validate a clinically relevant model of ETP-ALL, a newly identified subtype of highly lethal pediatric cancer with no known cause or cure. The proposed studies will also employ this innovative model system and human clinical samples to establish the role and mechanism by which PDLIM2, RelA and Ras interact in ETP-ALL pathogenesis. Completion of these studies will greatly increase our understanding of ETP-ALL pathogenesis and may lead to novel therapeutic strategies for this incurable pediatric leukemia.
|Zhou, J; Qu, Z; Yan, S et al. (2015) Differential roles of STAT3 in the initiation and growth of lung cancer. Oncogene 34:3804-14|