Abstract
Abstract 2501
T cell acute lymphoblastic leukemia (T-ALL) is the most common malignancy in children and accounts for nearly one third of all pediatric cancers. In this type of leukemia, lymphoid progenitor cells that are responsible for the generation of mature lymphocytes become genetically altered, leading to deregulated proliferation, survival, and clonal expansion. Two common genetic alterations frequently associated with this disease are mutations in the NOTCH1 cell-surface receptor and aberrant expression of the TAL1 transcription factor, with each abnormality detected in more than half of human T-ALL patients. The mutations in the NOTCH1 gene result in the aberrant activation of Notch signaling, a highly conserved signal transduction pathway that is critical for lymphocyte growth, maturation and survival. The constitutive activation of Notch signaling induces leukemia in mouse models and is required for human T-ALL leukemic cell growth and survival. On the other hand, TAL1 is required for the functions of hematopoietic stem cells and is essential for the generation of the erythroid and myeloid lineages. The ectopic activation of the TAL1 gene deregulates normal hematopoietic stem cell renewal and differentiation, leading to leukemia in cooperation with other oncogenes. Therefore, Notch and TAL1 oncogenic activities are critical for the initiation and maintenance of T-ALL.
In this study, we investigated the role of a transcriptional co-activator, MAML1, in regulating NOTCH1 and TAL1 transforming activities in leukemic cells. In addition to its known function in co-activating Notch signaling, we found that MAML1 is a novel interacting partner for TAL1. MAML1 also enhanced TAL1 transcriptional activities, suggesting a role for MAML1 in TAL1-regulated transcription and leukemogenesis. A subset of T-ALL leukemic cells exhibit aberrant activation in both the NOTCH1 and TAL1 activities; thus, it suggests that these two genetic alterations cooperate in promoting leukemic cell growth and survival. Indeed, we found that the combined inhibition of both the pathways (via the pharmacological blockade of Notch signaling and shRNA-mediated TAL1 knockdown) results in synergistic responses in leukemic cells that carry genetic alterations in both the NOTCH1 and TAL1 genes, indicating that the two pathways synergize in promoting T-ALL. Since MAML1 appears to be a common key regulator for both TAL1 and Notch1 pathways, we next determined whether MAML1 expression level affects leukemic cell growth and survival. Gene knockdown studies suggest that MAML1 is essential for leukemic cell growth and survival by possibly regulating NOTCH1 and TAL1-mediated transcription. Overall, our data reveals a novel common regulatory mechanism for both NOTCH1 and TAL1 oncogenic pathways, and suggest that the manipulation of MAML1 expression or functional activities will affect leukemia initiation and progression. Therefore, our current studies focus on assessing the MAML1 co-activator as a target for these two oncogenic pathways.
Disclosures:
Griffin: Novartis: Consultancy, Research Funding.
Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis