Fox and Blimp in NK-cell lymphoma

In this issue of Blood, Karube and colleagues have identified FOXO3 and PRDM1 (Blimp1) as tumor suppressor genes with a potentially critical role in the pathobiology of extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia.¹ 

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) and aggressive NK-cell leukemia (ANKL) are rare hematologic malignancies with an unfavorable prognosis and an increased prevalence in Asia and South America.²  Malignant cells are universally associated with the clonal episomal Epstein-Barr virus (EBV) form and frequently harbor numerous cytogenetic abnormalities. Wong et al³  identified a recurring deletion in the long arm of the chromosome 6q21q25 in NK-cell lymphoma/leukemia, suggesting that this region contained a putative tumor suppressor gene. Interestingly, deletions in the chromosome 6q21 have also been found in patients with solid tumors and B-cell lymphomas. The analysis of clinical samples and cell lines in diffuse large B-cell lymphoma (DLBCL) with del(6q21) identified mutations in several down-regulated candidate genes including PRDM1 (PR domain zinc finger protein 1), also known as Blimp-1 (B-lymphocyte-induced maturation protein).⁴  PRDM1 is a pleiotropic repressive transcription factor that is essential for the terminal differentiation of antibody-producing cells.⁵  For many years, it was believed that PRDM-1 is B cell–specific but more recent reports have suggested that it also plays a pivotal role in the regulation of NK-cell activation and maturation.⁶  Recently, several research teams have attempted to identify genes important in the pathogenesis of NK-cell lymphoma/leukemia.^7-9  Although numerous chromosomal gains and losses were detected in cell lines and clinical samples, a deletion in 6q21 was most frequent.⁷  Several candidate genes were found in a minimal common region (MCR) in 6q21 but no functional studies were conducted to confirm a tumor suppressor role.^7,8  Karube et al performed several key experiments to support their hypothesis that PRDM1 and forkhead transcription factors of the O class (FOXO3) are tumor suppressor gene candidates implicated in pathogenesis of ENKTL and ANKL.¹  First, they tested a relatively large number of clinical samples and cell lines, identifying 7 gene candidates in 2 MCRs in 6q21 chromosome. Second, they created a novel elegant experimental model to study the functional role of each gene. The re-expression of only 2 genes, FOXO3 and PRDM1, resulted in the inhibition of the proliferation of experimental NK cells. Third, they validated the results from the gene expression profiling and confirmed that FOXO3 and PRDM1 were down-regulated in a majority of the clinical samples and cell lines including the samples with the absence of del(6q21). Fourth, they discovered several nonsense mutations in PRDM1 and missense mutations in FOXO3, which is consistent with “2-hit” hypothesis. While the jury is still out on the role of other deleted genes in chromosome 6q21 in the pathogenesis of NK-cell malignancies, the implications from this report can be far-reaching

FOXO3 is a member of the FoxO family of transcription factors regulating numerous cellular processes.¹⁰  This factor has not been extensively studied in human lymphomas, but a recent study identified FOXO3 in the most frequently deleted MCR in chromosome 6q21 in several types of B-cell lymphoproliferative disorders.¹¹  In experimental animal studies, somatic deletions of all alleles of 3 FOXO members resulted in the development of progressive thymic T-cell lymphomas and hemangiomas.¹²  Because both FOXO3 and PRDM1 are transcription factors integrated in multiple intracellular signal transduction pathways, an understanding of the deregulation of these pathways in NK-cell lymphoma will be important for the identification of therapeutic targets and the development of effective treatment strategies.

However, as is common for any novel finding, many questions arise from this work. Is the down-regulation of FOXO3 and PRDM1 a primary or secondary event in lymphomagenesis? Is the inactivation or down-regulation of both tumor suppressors necessary for the development of the disease phenotype? What are the most frequent mechanisms responsible for down-regulation of FOXO3 and PRDM1 in patients with ENKTL and ANKTL without del(6q21)? What is the role of EBV in the pathogenesis of NK lymphomas and how it interacts with FOXO3 and PRDM1? In summary, there is no doubt that the work of Karube and colleagues is an important step forward in our understanding of the molecular pathogenesis of ENKTL and ANKL, which could open the door for exciting new research.