Original Article

Leukemia (2010) 24, 125–132; doi:10.1038/leu.2009.186; published online 17 September 2009

Chronic Lymphocytic Leukemia

A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence

N Darzentas1, A Hadzidimitriou1,2, F Murray3, K Hatzi4, P Josefsson5, N Laoutaris6, C Moreno7,8, A Anagnostopoulos2, J Jurlander5, A Tsaftaris1, N Chiorazzi4, C Belessi6, P Ghia9,10, R Rosenquist3, F Davi11 and K Stamatopoulos2

  1. 1Centre for Research and Technology Hellas, Institute of Agrobiotechnology, Thessaloniki, Greece
  2. 2Hematology Department and HCT Unit, G Papanicolaou Hospital, Thessaloniki, Greece
  3. 3Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
  4. 4The Feinstein Institute for Medical Research, North Shore–LIJ Health System, Manhasset, NY, USA
  5. 5Department of Hematology, Rigshospitalet, Copenhagen, Denmark
  6. 6Department of Hematology, Nikea General Hospital, Athens, Greece
  7. 7Institute of Hematology and Oncology, Hospital Clinic, University of Barcelona, Barcelona, Spain
  8. 8Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Barcelona, Spain
  9. 9Laboratory of B-Cell Neoplasia, Division of Molecular Oncology and Clinical Unit of Lymphoid Malignancies, Department of Oncology, Università Vita-Salute San Raffaele, Milan, Italy
  10. 10Istituto Scientifico San Raffaele, Milan, Italy
  11. 11Laboratory of Hematology, Hôpital Pitié-Salpètrière, Université Pierre et Marie Curie, Paris, France

Correspondence: Dr P Ghia, Department of Oncology, Università Vita-Salute San Raffaele, c/o DIBIT 4A3, Via Olgettina 58, Milano 20132, Italy. E-mail: ghia.paolo@hsr.it

Received 30 March 2009; Revised 4 July 2009; Accepted 23 July 2009; Published online 17 September 2009.

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Abstract

Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, ‘stereotyped’ B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of ‘stereotyped’ cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first (~30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells.

Keywords:

CLL, B-cell receptor, stereotypy, pattern, repertoire