POKEMON Is a Proto-Oncogene Which Plays a Key Role in Lymphomagenesis.

POKEMON (for POK, Erythroid, Myeloid ONtogenic factor, also known as LRF) was originally isolated as a homologue of PLZF (Promyelocytic Leukemia Zinc Finger) which can physically interact with the BCL6 (B Cell Lymphoma 6) proto-oncogene.

Analysis of Pokemon−/− mice demonstrates that this transcriptional repressor plays a key developmental role whose function is required for cellular differentiation in multiple tissues such as skin, adipose tissue and hematopoietic lineage cells. Taking advantage of Pokemon−/− MEFs (Mouse Embryonic Fibroblasts), we found that Pokemon is indispensable for cellular transformation mediated by oncogenes (such as BCL6, E1A, H-RasV12, c-Myc, or T-Ag) and Pokemon overexpression overcomes oncogene induced premature senescence and apoptosis leading to oncogenic transformation by repressing p19ARF tumor suppressor. Furthermore, Pokemon−/− MEFs showed a premature senescence phenotype in early passage which was rescued by inactivation of p19ARF. To explore the oncogenic role of Pokemon in vivo, we generated Lck/Eμ Pokemon transgenic mice in which Pokemon is over expressed in T and B lineage cells under the control of Lck/Eμ promoter/enhancer. Strikingly, about 50% of the mice developed T lymphoblastic lymphoma (CD4+, CD8+, CD44 + and TdT+) after a latent period of 2 to 4 months. As Pokemon expression proved essential for cellular transformation and is oncogenic when overexpressed in vivo, we analyzed the levels of POKEMON expression in human cancers, performing Tissue Microarray Analysis (TMA). We first analyzed human B-cell lymphomas as POKEMON is normally co-expressed with BCL6 in the B-cell within the germinal center, and may therefore cooperate with BCL6 in lymphomagenesis. We analyzed and scored a total of 123 cases of diffuse large B-cell lymphoma (DLBCL) and 290 cases of follicular lymphoma (FL) for POKEMON protein expression levels. POKEMON was highly expressed in 25–35% and moderately expressed in 40–50% of both DLBCL and FL clinical samples. Strikingly, as previously shown for BCL6, POKEMON positivity predicted a better prognosis of overall survival in DLBCL. Interestingly, the vast majority (approximately 80%) of BCL6 positive DLBCLs and FLs were found to be POKEMON positive. By contrast, not all the POKEMON positive lymphomas expressed BCL6. Importantly, coexpression of POKEMON and BCL6 in DLBCL predicted an even better clinical outcome, identifying a clinically distinct DLBCL subtype.