Identification of genetic alterations occurring in pre-tcell receptor (TCR)-deficient leukemia

Al-Dalali, Faiza Ahmed Ahmed

http://hdl.handle.net/10400.1/3780

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Authors

Al-Dalali, Faiza Ahmed Ahmed

Advisor(s)

Santos, Nuno Rodrigues dos

Abstract(s)

T-cell acute lymphoblastic leukemia (T-ALL) is a thymocyte malignancy. Although the identification of several genetic alterations in this leukemia has allowed a better understanding of how it develops, more research is required to develop more efficient therapies. The pre-T cell receptor (pre-TCR) complex has been characterized structurally and functionally and is an essential player in T-cell development. However, its contribution to T-cell leukemogenesis remains controversial. Indeed, reports have noticed the importance of the pre-TCR in some mouse models of T-cell leukemia. T-ALL mouse models are useful to study the cellular and molecular mechanisms underlying this disease. Regarding the TEL-JAK2 transgenic mouse model, it was found that the absence of the pre-TCR complex from T lymphocytes led to a significant delay in T-ALL onset. A genomic DNA analysis by array comparative genomic hybridization (aCGH) revealed that late-onset pre-TCR-negative leukemias presented more genomic alterations (gains and losses of DNA) than early-onset pre-TCR-positive leukemias, indicating that these alterations can occur and be selected to compensate for the absence of pre-TCR. The goal of this project was to identify genes aberrantly expressed in pre-TCR-negative leukemia. To this end, the copy number of candidate genes were compared between leukemic cells from regular TEL-JAK2 mice and TEL-JAK2 mice without the Rag2 gene, which is essential for the pre-TCR complex formation. The Cdkn2a, Cdkn2b, Myc, Ikaros, Pten, Bcl11b, and Fbxw7 genes, which are localized in genomic regions previously found to be altered in pre-TCR-deficient leukemic cells and/or are involved in cancer, have been analyzed. By performing quantitative PCR (qPCR) we found DNA copy number alterations in TEL-JAK2;Rag2-/- leukemia DNA as compared to regular TEL-JAK2 leukemia DNA in the same genomic regions that showed chromosomal abnormality in aCGH analysis. Further studies need to be performed to better understand the precise role of pre-TCR in T-ALL and the role of compensatory mechanisms occurring in the absence of pre-TCR.