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Chronic Lymphocytic Leukemia
Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations
Andreas Agathangelidis,1* Viktor Ljungström,2* Lydia Scarfò,1 Claudia Fazi,1 Maria Gounari,1,3 Tatjana Pandzic,2 Lesley-Ann Sutton,2,4
Kostas Stamatopoulos,3 Giovanni Tonon,5 Richard Rosenquist2,4**
and Paolo Ghia1**
1Strategic Research Program on CLL and B-cell Neoplasia Unit, Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy; 2Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden; 3Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece; 4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden and 5Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS Istituto Scientifico San Raffaele, Milan, Italy
ABSTRACT
Despite the recent discovery of recurrent driver mutations in chron- ic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per- formed whole-genome sequencing in 11 individuals with monoclonal B- cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indis- tinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not fre- quently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclon- al B-cell lymphocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unre- ported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.
Introduction
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the West, is a clinically heterogeneous disease.1 At one end of the spectrum, CLL patients present with an indolent disease that does not require therapy for decades. At the other end of the spectrum, patients experience a rapidly progres- sive disease, need early treatment, and frequently relapse.2,3
High-throughput studies14,15 have established that, though displaying a markedly lower mutational burden compared to solid tumors,16 CLL is characterized by a diverse genetic landscape with driver gene mutations in pathways considered cen- tral for disease pathogenesis, e.g. NOTCH and NF-κB signaling.7,9,17 The frequency of most driver gene mutations in CLL tends to increase in aggressive/refractory cases supporting their involvement mainly in disease progression.18-20
Chronic lymphocytic leukemia is preceded by a condition termed monoclonal B-cell lymphocytosis (MBL) that is characterized by the presence of circulating monoclonal B cells with a CLL phenotype, however, at a lower concentration than
Ferrata Storti Foundation
Haematologica 2018 Volume 103(5):865-873
*AA and VL contributed equally as first authors. **RR and PG contributed equally as last authors
Correspondence:
ghia.paolo@hsr.it
Received: August 8, 2017. Accepted: February 7, 2018. Pre-published: February 15, 2018.
doi:10.3324/haematol.2017.177212
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/865
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