LYMPHOID NEOPLASIA MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes

Aberrant overexpression of the miR17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 downregulates the proapoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR17-92 into 2 genetically distinct B-cell lymphoma cell lines: Raji, which overexpress c-Myc, and SUDHL4, which overexpress Bcl2. Raji transfected with miR-17-19b-1 exhibited down-regulated expression of Bim and a slight up-regulation in Bcl2 expression. On the other hand, SUDHL4 transfectants showed aggressive cell growth reflecting facilitated cell cycle progression at the G1 to S transition and decreased expression of CDKN1A mRNA and p21 protein (CDKN1A/ p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR20a into Jeko-1 led to up-regulation of CDKN1A/p21, resulting in decreased cell growth with G1 to S arrest. Thus, CDKN1A/ p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the miR-17-92 polycistron has distinct targets in different B-cell lymphoma subtypes. (Blood. 2009;113:396-402)