The role of TLE4 as a tumor suppressor in acute myeloid leukemia and regulator of hematopoietic and bone development
Shin, Thomas H.
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The presence of AML1-ETO (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, is a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). Although AML1-ETO is able to block differentiation and immortalize hematopoietic stem cells, other contributory events are required for cell proliferation and leukemogenesis, suggesting that specific tumor suppressor genes may counteract the leukemic potential of AML1-ETO. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of TLE4 as a key cooperating event in the development of AML1-ETO AML, leading to increased cell proliferation, blocked apoptosis and differentiation, as well as cytarabine resistance in leukemic cells. This suggested TLE4 functions as a tumor suppressor gene in AML.We found these effects are mediated by the loss of TLE4 regulation of a COX-Wnt inflammatory axis. These effects were consequently reversible by Wnt signaling and cyclooxygenase inhibition, pointing towards anti-inflammatory agents as potentially new therapeutic and adjuvant strategies for AML. While studies in Drosophila implicate TLE/Groucho as a key mediator of various signaling pathways, including receptor tyrosine kinase/Ras/MAPK, Notch, Myc, and Wnt pathways, there is surprisingly little known about the role of TLE in mammalian development. Using a Tle4 knockout (T4KO) mouse, we identified previously unknown roles for Tle4 in regulating vertebrate mammalian hematopoietic and bone development. T4KO mice manifest leukocytopenia and defective hematopoietic stem cell populations. Using serial transplantation and stromal co-culture, we find that these hematopoietic deficiencies arise due to both intrinsic dysfunction of hematopoietic stem cells as well as defective extrinsic regulation of hematopoiesis by the stem cell niche. Additionally, T4KO mice are severely runted and exhibit markedly decreased bone mineralization concomitant with defective osteoblast function and decreased mineral apposition rates. Many of the pathways regulated by TLE are aberrant in cancer, which has led to increasing studies connecting TLE with various malignancies, including synovial cell sarcoma and glioblastoma. Our findings have great implications for current understanding of TLE function in not only cancer, but also bone and hematopoietic development.