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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.

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