Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

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Blank Published online 26 August 2010

Haematologica, Vol 95, Issue 12, 2072-2079 doi:10.3324/haematol.2010.028639

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia

expressing stereotyped IGHV4-34 B-cell receptors

Millaray Marincevic1,*, Mahmoud Mansouri1,*, Meena Kanduri1, Anders Isaksson2,

Hanna Göransson2, Karin Ekström Smedby3, Jesper Jurlander4, Gunnar Juliusson5,

Fred Davi6, Kostas Stamatopoulos7,8, Rosenquist1

1 Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

2 Department of Medical Sciences, Cancer Pharmacology and Informatics, Uppsala

University, Uppsala, Sweden

3 Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet,

Stockholm, Sweden

4 Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen,

Denmark

5 Lund Strategic Research Center for Stem Cell Biology and Cell Therapy,

Hematology and Transplantation, Lund University, Lund, Sweden

6 Laboratoire d’Hématologie, Hôpital Pitié-Salpêtrière et Université Pierre et

Marie Curie, Paris, France

7 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki,

Greece

8 Institute of Agrobiotechnology, Center for Research and Technology,

Thessaloniki, Greece

Correspondence: Rosenquist, MD, PhD, Department of Genetics and

Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

Phone: international +46.18.6115947., Fax: international +46.18.554025., E-mail:

richard.rosenquist@...

Background: Numerous subsets of patients with chronic lymphocytic leukemia

display similar immunoglobulin gene usage with almost identical complementarity

determining region 3 sequences. Among IGHV4-34 cases, two such subsets with

" stereotyped " B-cell receptors were recently identified, i.e. subset #4

(IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients

appear to share biological and clinical features, e.g. young age at diagnosis

and indolent disease, whereas little is known about subset #16 at a clinical

level.

Design and Methods: We investigated the global gene expression pattern in sorted

chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients

using Affymetrix gene expression arrays.

Results: Although generally few differences were found when comparing subset to

non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed

for subset #4 versus subset #16. The differentially expressed genes,

predominantly with lower expression in subset #4 patients, are involved in

important cell regulatory pathways including cell-cycle control, proliferation

and immune response, which may partly explain the low-proliferative disease

observed in subset #4 patients.

Conclusions: Our novel data demonstrate distinct gene expression profiles among

patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence

for biological differences in the pathogenesis of these subsets and underscoring

the functional relevance of subset assignment based on B-cell receptor sequence

features.