The basic helix-loop-helix (bHLH) TAL oncoprotein is found to be aberrantly expressed in a large fraction of human acute lymphoblastic leukemias (T-ALL) as a result of chromosomal rearrangements. Overexpression of TAL in transgenic mice induces T cell lymphoma. Although TAL can form heterodimers with the ubiquitously expressed bHLH E proteins (E2A, E2-2 and HEB), no significant transactivating activities of the heterodimers have been detected by the investigator and others. Recently, she has shown that TAL lacks transactivation domains compatible with the E proteins to activate transcription. Therefore, when TAL forms complexes with the E proteins, it may inhibit gene expression activated by the homodimers of E proteins. The E proteins, particularly E2A, have been shown to be involved not only in the differentiation of a wide variety of cell types but also in growth suppression when overexpressed in NIH3T3 fibroblasts. The investigator has shown that E2A can directly activate the transcription of the p21 gene, which encodes a universal inhibitor of cyclin dependent kinases essential for cell cycle progression. Interestingly, disruption of the E2A gene also leads to T cell lymphoma in mice. These findings prompt her to propose a molecular mechanism involved in TAL-induced leukemogenesis; i.e. when TAL is aberrantly expressed in T cells, it inhibits the growth suppressing function of E proteins and causes cell transformation. Experiments outlined in this proposal intend to test her hypothesis and to distinguish it from the current perception that TAL/E protein heterodimers activate unknown genes that result in leukemogenesis. She plans to use two biological systems in the study: TAL-expressing T cell lines derived from human T-ALL and TAL-expressing transgenic mice.
The specific aims i nclude (1) to determine the role of TAL in the proliferation of T-ALL cell lines and the mechanisms involved, (2) to investigate the mechanism of TAL-induced leukemogenesis in transgenic mice, and (3) to identify specific genes activated by E47 in T cell lines and inhibited by TAL in T cell lymphomas in the TAL transgenic mice.
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