PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma

Abstract

Key Points• The commonest lesions in anaplastic large cell lymphomas are losses at 17p13 and at 6q21, concomitant in up to onequarter of the cases. • PRDM1 (BLIMP1) gene (6q21) is inactivated by multiple mechanisms and acts as a tumor suppressor gene in anaplastic large B-cell lymphoma.Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK 1 and ALK 2 ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK 2 ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK 2 ALCL, and in 29% of all ALCL cases with a clinical implication. (Blood. 2013;122(15):2683-2693

Aspects moléculaires des lymphomes T périphériques (1)

“…Ce gène jouerait également un rôle important dans l'homéostasie T et la tolérance du soi [82,83]. La réexpression de PRDM1 dans des lignées cellulaires avec une délétion 6q21 conduit à un arrêt de la prolifération cellulaire in vitro et à une diminution de la croissance tumorale dans des modèles de xénogreffe, indiquant que PRDM1 agit comme un gène suppresseur de tumeur [75]. La perte de la région 6q21 est significativement associée à la perte en 17p13.3-p12.…”

“…La perte de la région 6q21 est significativement associée à la perte en 17p13.3-p12. Néanmoins, les mutations du gène TP53 sont rares chez les patients atteints de LAGC ALK -(elles ne concernent que 5 % des cas) [75,76]. Les LAGC ALK -avec inactivation de PRDM1 et/ou perte en 17p se caractérisent par une survie globale inférieure à celle des autres groupes [75].…”

“…Les LAGC ALK -avec inactivation de PRDM1 et/ou perte en 17p se caractérisent par une survie globale inférieure à celle des autres groupes [75]. [75,76]. Cette inactivation est le plus souvent monoallélique, suggérant un possible effet d'haplo-insuffisance.…”

“…Cette inactivation est le plus souvent monoallélique, suggérant un possible effet d'haplo-insuffisance. Il n'a pas été observé de méthylation du promoteur de l'autre copie [75]. …”

Anaplastic large cell lymphoma, ALK-negative

“…Copy number losses involving PRDM1 (6q21) and/or TP53/ (17p13) are recurrent in ALCL, ALKnegative, and have been associated with poor survival (Boi, Rinaldi et al 2013). Recurrent chromosomal rearrangements involving the DUSP22 -IRF4/ locus on 6p25.3 are present in ~30% of ALCL, ALK-negative (Feldman, Law et al 2009;Feldman, Dogan et al 2011;Parrilla Castellar, Jaffe et al 2014).…”