Reduction of Prep1 Levels Affects Differentiation of Normal and Malignant B Cells and Accelerates Myc Driven Lymphomagenesis

Abstract

The Prep1 homeodomain transcription factor has recently been recognized as a tumor suppressor. Among other features, haploinsufficiency of Prep1 is able to strongly accelerate the B-lymphomagenesis in EμMyc mice. Now we report that this occurs concomitantly with a change in the type of B-cell lymphomas generated by the Myc oncogene. Indeed, the tumors generated in the EμMyc-Prep1+/− mice are much more immature, being mostly made up of Pro-B or Pre-B cells, while those in the EμMyc-Prep1+/+ mice are more differentiated being invariably IgM+. Moreover, we show that Prep1 is in fact required for the differentiation of Pro-B and Pre-B cells into IgM+ lymphocytes and/or their proliferation, thus showing also how a normal function of Prep1 affects EμMyc lymphomagenesis. Finally, we show that the haploinsufficiency of Prep1 is accompanied with a major decrease of Myc-induced apoptosis and that the haploinsufficieny is sufficient for all these effects because the second allele of Prep1 is not lost even at late stages. Therefore, the tumor-suppressive activity of Prep1 is intertwined with both the interference with Myc-induced apoptosis as well as with natural developmental functions of the protein.

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

“…S1). These data indicate that the oncosuppressor activity of PREP1 is exerted also in lung tumor cells, in agreement with our previous data in a system of MYC-induced lymphomagenesis (8,28).…”

“…S1) agrees with our previous findings (8,27,28), the proinvasive and prometastatic functions of PREP1 are novel. PREP1 induces the EMT hallmarks-downregulation of E-cadherin and up-regulation of vimentinalong with cytoskeleton remodeling, increased motility, and invasiveness in lung adenocarcinoma cells.…”

“…8) might result from the increased metastatic potential of PREP1 + lung tumors, despite the inhibitory effect of PREP1 on primary tumor growth suggested by our present (SI Appendix, Fig. S1) and previous (8,27,28) findings.…”

“…The invasive and metastatic phenotype triggered by PREP1 overexpression in lung adenocarcinoma cells is at odds with the tumor-suppressive role of PREP1 (8,28). However, the novel function of PREP1 as regulator of the TGF-β pathway can explain the apparent discrepancy.…”

Pknox1/Prep1 Regulates Mitochondrial Oxidative Phosphorylation Components in Skeletal Muscle

“…Generation of Prep1 hypomorphic and Prep1-loxP mice was described elsewhere (8,12). Briefly, Prep1 hypomorphic mice have a retroviral vector (VICTR45) inserted into intron 1, and Prep1-loxP mice have loxP sites flanking exons 6 and 7 of the Prep1 gene.…”