hes1-protein--human and Leukemia--T-Cell

It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Growth Processes; Cell Survival; Deubiquitinating Enzyme CYLD; Genes, Tumor Suppressor; Homeodomain Proteins; Humans; Leukemia, T-Cell; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Receptors, Notch; Signal Transduction; Transcription Factor HES-1; Transcription Factor RelA; Tumor Suppressor Proteins

Notch receptors are conserved regulators of cell fate and have been implicated in the regulation of T cell differentiation and lymphomagenesis. However, neither the generality of Notch involvement in leukemia, nor the molecules with which Notch may interact have been clarified. Recently, we showed that transgenic mice expressing the constitutively active intracellular domain of Notch3 in thymocytes and T cells developed early and aggressive T cell neoplasias. Although primarily splenic, the tumors sustained features of immature thymocytes, including expression of pTalpha, a defining component of the pre T cell receptor, known to be a potent signaling complex provoking thymocyte survival, proliferation, and activation. Thus, enforced expression of Notch3, which is ordinarily down-regulated as thymocytes mature, may sustain pre T cell receptor expression, causing dysregulated hyperplasia. This hypothesis has been successfully tested in this article by the observation that deletion of pTalpha in Notch3 transgenic mice abrogates tumor development, indicating a crucial role for pTalpha in T cell leukemogenesis. Parallel observations were made in humans, in that all T cell acute lymphoblastic leukemias examined showed expression of Notch3 and of the Notch target gene HES-1, as well as of pTalpha a and b transcripts, whereas the expression of all these genes was dramatically reduced or absent in remission. Together, these results suggest that the combined expression of Notch3 and pTalpha sustains T cell leukemogenesis and may represent pathognomonic molecular features of human T-ALL.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Transformation, Neoplastic; Child; Flow Cytometry; Gene Deletion; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Immunophenotyping; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Lymph Nodes; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, Transgenic; Proto-Oncogene Proteins; Receptor, Notch1; Receptor, Notch3; Receptor, Notch4; Receptors, Antigen, T-Cell; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Cell Surface; Receptors, Notch; RNA, Messenger; Spleen; Thymus Gland; Transcription Factor HES-1; Transcription Factors