Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients

January 5, 2008

J. Clin. Invest. 118:306-315 (2008). doi:10.1172/JCI32625.

Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of

chronic lymphocytic leukemia patients

C. Tschumper1, M. Geyer2, E. 2, Neil E. Kay3, Tait D.

Shanafelt3, Clive S. Zent3, Grzegorz S. Nowakowski3, G. Call3, Gordon W.

Dewald4 and Diane F. Jelinek1

1Department of Immunology, 2Department of Health Sciences Research, 3Department

of Internal Medicine, and 4Department of Laboratory Medicine and Pathology, Mayo

Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Address correspondence to: Diane F. Jelinek, Department of Immunology,

Guggenheim 4, Mayo Clinic College of Medicine, 200 First St. SW, Rochester,

Minnesota 55905, USA. Phone: (507) 284-5617; Fax: (507) 266-0981; E-mail:

jelinek.diane@... .

Received for publication May 8, 2007, and accepted in revised form October 17,

2007.

Survival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be

predicted by analysis of mutations in the immunoglobulin heavy chain variable

gene (IGHV). Patients without mutations (unmutated [uM]) are at greater risk for

disease progression and death than patients with mutations (M). Despite this

broad prognostic difference, there remains wide intragroup variation in the

clinical outcome of UM patients, especially those with low/intermediate Rai risk

disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to

determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining

(IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM

patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly

shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3

gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was

the best single prognostic factor for TTT; however, IGHD usage was also a

significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have

prognostic relevance in UM B-CLL patients with low/intermediate Rai risk

disease. In addition, these data support the concept that antigen-driven

selection of specific Ig receptors plays a role in the clinical course of B-CLL.

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