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

Abstract

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 (Prep1i/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. Prep1i/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 Prep1i/i background appears to favor the insurgence of mutations that cause a more aggressive Meis1-HoxA9-generated leukemia. Indeed, the Prep1i/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 Prep1i/i background is the post-transcriptional increase in Meis1 protein level.

The miR-17∼92 cluster contributes to MLL leukemia through the repression of MEIS1 competitor PKNOX1

“…Recent studies by the Blasi group support and complement our findings [43, 44]. They found that Prep1 (Pknox1) competes with Meis1 for binding to Pbx1, and Prep1 depletion enabled Meis1 to transform MEFs [43].…”

“…They found that Prep1 (Pknox1) competes with Meis1 for binding to Pbx1, and Prep1 depletion enabled Meis1 to transform MEFs [43]. Additionally, depletion of Prep1 accelerated the onset of Meis1-Hoxa9 -mediated leukemogenesis in a murine model [44]. They hypothesized that increasing PREP1 levels may be an important area for future therapeutic development [43].…”

“…This includes regulation of HOX-PBX-MEIS complexes. Both HOXA9 and MEIS1 are directly regulated by MLL and are necessary for MLL leukemia development [3, 22, 44, 46] MiRNAs in the miR-17~92 cluster are also overexpressed in MLL leukemia. Here we show that miR-17-5p and miR-19a-3p of the miR-17~92 cluster target PKNOX1 and that antagonizing these miRNAs causes increased PKNOX1 expression.…”

Deregulation of the HOXA9/MEIS1 axis in acute leukemia

“…The oncogenic properties of MEIS1 are antagonistically regulated by PREP1, another TALE family protein, through direct competition for binding sites (68). PREP1 also competitively heterodimerizes and sequesters PBX proteins, thereby decreasing stability of MEIS1 and preventing the MEIS1-DDX3x/DDX5 interactions that are required for tumorigenesis (69, 70). Furthermore, in vivo leukemogenesis studies with HOXA9/MEIS1 in PREP1-deficient cells showed more aggressive leukemias compared to wild-type (69).…”

Loss of the Homeodomain Transcription Factor Prep1 Perturbs Adult Hematopoiesis in the Bone Marrow

“…Meis1 cooperates with HoxA9 in leukemogenesis, as its overexpression accelerates the emergence of HoxA9 -induced acute myeloid leukemia [ 37 ], whereas Prep1 overexpression does not accelerate HoxA9 -induced leukemia but rather delays its onset [ 38 ]. Acceleration of Meis-HoxA9 -induced leukemia on a Prep1 -hypomorphic background has also been reported [ 39 ]. Therefore, in order to interpret the hematopoietic phenotype of our Prep1-CKO mice, the complex interactions of each of these three TALE family members must be taken into account, as their patterns of interaction affect gene activation and/or inhibition, as well as each other’s protein stability, all of which can lead to different biological outcomes.…”