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Chronic Lymphocytic Leukemia
Trisomy 12 chronic lymphocytic leukemia expresses a unique set of activated and targetable pathways
Lynne V. Abruzzo,1* Carmen D. Herling,2 George A. Calin,3 Christopher Oakes,4 Lynn L. Barron,5 Haley E. Banks,5 Vikram Katju,6 Michael J. Keating7
and Kevin R. Coombes6*
1Department of Pathology, The Ohio State University, Columbus, OH, USA; 2Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Germany; 3Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 4Department of Internal Medicine, The Ohio State University, Columbus, OH, USA; 5Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA and 7Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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 mor- phological 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 thrombocytope- nia, 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 con- tributes 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 com- pared cases with +12 as the only cytogenetic abnormality to cases with only del(13q), del(11q), or diploid cytogenetics using independent dis- covery (n=97) and validation (n=50) sets. We demonstrate that CLL cases with +12 as the sole abnormality express a unique set of activated path- ways 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.
Introduction
Chromosomal abnormalities, predominantly gains and losses, are strong predic- tors of disease progression and survival in chronic lymphocytic leukemia (CLL). Fluorescence in situ hybridization (FISH) assays on interphase nuclei have demon- strated that approximately 80% of cases contain non-random gains or losses of chromosomal material, many with prognostic significance.1 Deletions in 13q14 (del(13q)) are most common, followed by deletions in 11q22.3-q23.1 (del(11q)), tri- somy 12 (+12), and deletions in 6q21-q23 (del(6q)) and 17p13 (del(17p)).1 Del(13q), associated with a good prognosis, is the site of the microRNA genes, miR-15a/16-1, which negatively regulate BCL2 post-transcriptionally.2 Their dele- tion results in overexpression of the anti-apoptotic protein BCL2. In contrast,
Ferrata Storti Foundation
Haematologica 2018 Volume 103(12):2069-2078
*LVA and KRC contributed equally to this study
Correspondence:
lynne.abruzzo@osumc.edu
Received: February 5, 2018. Accepted: June 29, 2018. Pre-published: July 5, 2018.
doi:10.3324/haematol.2018.190132
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/2069
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