Trisomy 12 chronic lymphocytic leukemia expresses a unique set of activated and targetable pathways

Abstract

Although trisomy 12 (+12) chronic lymphocytic leukemia (CLL) comprises about 20% of cases, relatively little is known about its pathophysiology. These cases often demonstrate atypical morphological and immunophenotypic features, high proliferative rates, unmutated immunoglobulin heavy chain variable region genes, and a high frequency of NOTCH1 mutation. Patients with +12 CLL have an intermediate prognosis, and show higher incidences of thrombocytopenia, Richter transformation, and other secondary cancers. Despite these important differences, relatively few transcriptional profiling studies have focused on identifying dysregulated pathways that characterize +12 CLL, and most have used a hierarchical cytogenetic classification in which cases with more than one recurrent abnormality are categorized according to the abnormality with the poorest prognosis. In this study, we sought to identify protein-coding genes whose expression contributes to the unique pathophysiology of +12 CLL. To exclude the likely confounding effects of multiple cytogenetic abnormalities on gene expression, our +12 patient cohort had +12 as the sole abnormality. We profiled samples obtained from 147 treatment-naïve patients. We compared cases with +12 as the only cytogenetic abnormality to cases with only del(13q), del(11q), or diploid cytogenetics using independent discovery (n=97) and validation (n=50) sets. We demonstrate that CLL cases with +12 as the sole abnormality express a unique set of activated pathways compared to other cytogenetic subtypes. Among these pathways, we identify the NFAT signaling pathway and the immune checkpoint molecule, NT5E (CD73), which may represent new therapeutic targets.

Figure 1.

Kaplan Meier plots stratified by cytogenetic subtype. (A) Time to treatment, and (B) progression-free survival.

Figure 2.

Results of two-way clustering according to cytogenetic subtype using the genes found to be differentially expressed. The samples include 40 del(13q) (blue), 32 diploid (brown), 10 del(11q) (pink), and trisomy 12 (+12) (green). Each column is one sample; each row contains the standardized log expression values for one gene.

Figure 3.

Construction of a specific trisomy 12 (+12) CLL gene expression network. Genes indicated in blue are over-expressed in +12 chronic lymphocytic leukemia compared to other cytogenetic subtypes. Genes indicated in orange are under-expressed in +12 CLL. Genes indicated in gray are not differentially expressed. Brighter colors are more statistically significant; duller colors are less statistically significant. Genes on chromosome 12 are indicated by hexagons; genes located on other chromosomes are indicated by rectangles.