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The Deficiency of Tumor Suppressor Prep1 Accelerates the Onset of Meis1- Hoxa9 Leukemogenesis

Prep1 and Meis1 ortholog TALE transcription factors have opposing roles in tumorigenesis: Meis1 serves as an oncogene, Prep1 as a tumor suppressor. We now report that, Meis1 overexpression in primary Prep1-deficient (Prep1(i/i)) embryonic hematopoietic cells increases self-renewal potential of cells...

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Detalles Bibliográficos
Autores principales: Dardaei, Leila, Modica, Livia, Iotti, Giorgio, Blasi, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014505/
https://www.ncbi.nlm.nih.gov/pubmed/24809472
http://dx.doi.org/10.1371/journal.pone.0096711
Descripción
Sumario:Prep1 and Meis1 ortholog TALE transcription factors have opposing roles in tumorigenesis: Meis1 serves as an oncogene, Prep1 as a tumor suppressor. We now report that, Meis1 overexpression in primary Prep1-deficient (Prep1(i/i)) embryonic hematopoietic cells increases self-renewal potential of cells in vitro but not in vivo, whereas leukemia is instead obtained when Meis1 is combined with another oncogene, HoxA9. Prep1(i/i) Meis1-HoxA9-generated leukemic cells are less differentiated and grow more aggressively after the second passage in the mouse. These data indicate that Prep1 represents a barrier to the transforming activity of Meis1 in vitro, but its absence is not sufficient to induce early leukemogenesis. On the other hand, the Prep1(i/i) background appears to favor the insurgence of mutations that cause a more aggressive Meis1-HoxA9-generated leukemia. Indeed, the Prep1(i/i) leukemic cells upregulate the Polycomb protein Bmi-1 and expectedly down-regulate the Ink4a/Arf locus products. Finally, an important feature contributed by the Prep1(i/i) background is the post-transcriptional increase in Meis1 protein level.