TEL/AML1 Expression in a Non-B Cell Line Induces a Set of Differentially Expressed Genes, but Points to Cell Type Specific Effects of the Fusion Protein in Leukemic Blasts of TEL/AML1 Positive Patients.

Acute lymphoblastic leukemia (ALL) is the predominant malignancy in childhood (30%). The majority of ALL (75%) exhibit characteristic chromosomal aberrations with prognostic significance that are used to classify the heterogenic disease into subgroups. Among these, the translocation t(12;21) resulting in the fusion of the TEL and AML1 genes is the most frequent chromosomal rearrangement in childhood ALL (20 – 25%). Both genes code for transcription factors essential for normal hematopoiesis. Whereas AML1 functions mostly as an activator of expression, TEL/AML1 acts as a repressor in a dominant manner. To date, detailed knowledge on the effect of TEL/AML1 in the process of malignant transformation is widely lacking. To address the consequence of TEL/AML1 expression, we established stable TEL/AML1 expressing cell lines of B lymphoblastoid and non-B cell origin using an episomal vector system and performed microarray-based gene expression profiling. To this end, we obtained gene expression profiles of a TEL/AML1 expressing non-B cell clone and the corresponding empty vector control. We first set out to gain a measure for the comparability of gene expression profiles in leukemic cells of TEL/AML1 positive ALL patients and the TEL/AML1 expressing non-B cell line. We therefore used published gene expression data of initial and relapsed ALL to calculate diagnostic gene expression signatures that faithfully predict genetic and immunological ALL subtypes in patient samples. We then used these signatures to classify a test set of patient samples and the TEL/AML1 expressing non-B cell into these subtypes. All patient samples were predicted correctly, however, the TEL/AML1 non-B cell line was not classified as TEL/AML1 positive, indicating that the diagnostic signature of TEL/AML1 positive leukemic cells is not induced by TEL/AML1 in the non-B cell line. Nevertheless, we identified several genes differentially expressed in the non-B cell line as compared to the empty vector control. The majority of genes are down-regulated, in agreement with the repressor function of the fusion protein. Among these genes are several transcription factors and genes playing a role in hematopoietic development and immune response. Furthermore, we found several genes with a role in neuronal development and disease. Interestingly, TEL knock out mice die during embryonal development due to apoptosis of mesenchymal and neuronal cells, supporting a function of TEL in the nervous system. Thus, a set of genes is regulated by TEL/AML1 in a non-B cell line, compatible with the proposed functions of TEL and AML1. However, the diagnostic signature of leukemic blasts of TEL/AML1 positive ALL patients was not induced in these cells supporting the view that besides common changes in gene expression cell type specific effects of TEL/AML1 exist and contribute to leukemogenesis.