MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma

Anaplastic large cell lymphomas (ALCLs) encompass at least two systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide miRNA profiling on ALK(+)ALCLs (n=33), ALK(-)ALCLs (n=25), angioimmunoblastic T-cell lymphoma (n = 9), peripheral T-cell lymphoma, not otherwise specified (n=11) and normal T-cells and demonstrated that ALCL express many of the miRNAs that are highly expressed in normal T-cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS and the AITL subtype of PTCL. Cases of ALK(+)ALCL and ALK(-) ALCL were interspersed in unsupervised analysis suggesting a close relationship at molecular level. We identified a miRNA signature of seven miRNAs (five upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b and two down-regulated: miR-146a, miR-155) significantly associated with ALK(+)ALCL cases. In addition, we derived an 11 miRNA signature (four up-regulated: miR-210, miR-197, miR-191, miR-512-3p and seven down-regulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(-)ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs that was associated with ALK expression. Of these the miR-17~92 cluster and its paralogues were also highly expressed in ALK(+)ALCL and may represent important downstream effectors of the ALK oncogenic pathway.