Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL

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Blood First Edition Paper, prepublished online April 18, 2008; DOI

10.1182/blood-2008-03-142349.

Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through

analysis of IgVH gene usage and mutation status in familial CLL

Dalemari Crowther, Ruth Wild, le Sellick, J. S. Dyer, Francesca R

Mauro, J.G Cuthbert, Viggo Jonsson, Estella Matutes, Dearden,

Wiley, Fuller, Catovsky, and S Houlston*

Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom

MRC toxicology Unit, Leicester University, Leicester, United Kingdom

Division of Hematology, Dipartmento di Biotechnologie Cellulari ed Ematologia,

University " La Sapienza " , Rome, Italy

Department of Haematology, Belfast City Hospital, Belfast, United Kingdom

Department of Haematology, Aker University Hospital, University of Oslo, Oslo

Royal Marsden Hospital, Sutton, United Kingdom

Department of Medicine, Sydney University, Nepean Hospital, Penrith, Australia

Section of Haemato-Oncology, Institute of Cancer Research, Sutton, United

Kingdom

Section of Cancer Genetics, Insitute of Cancer Research, Sutton, United Kingdom

* Corresponding author; email: richard.houlston@... .

To address the proposition that familial B-cell chronic lymphocytic leukemia

(CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to

immunoglobulin gene usage or ontogenic development we compared immunoglobulin

(Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327

cases of CLL from 214 families, with 724 sporadic cases. The frequency of

mutated CLL was higher in familial CLL (P<0.001) and there was evidence of

intra-familial concordance in mutation status (P<0.001). The repertoire and

frequency of IgVH usage was, however, not significantly different between

familial and sporadic CLL. Furthermore, IgVH usage was not correlated between

affected members of the same family. These observations provide evidence that

familial CLL is essentially indistinguishable from sporadic CLL favoring a

genetic basis to disease development in general rather than a simple

environmental etiology.