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© The Rockefeller University Press, 0022-1007/1997/4/1435/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 8, April 21, 1997 1435-1446

Article

Lack of Allelic Exclusion in B Cell Chronic Lymphocytic Leukemia

Laura Z. Rassenti and Thomas J. Kipps

From the Division of Hematology/Oncology, Department of Medicine, University of California at San Diego, La Jolla, California 92093-0663

We determined the immunoglobulin (Ig) VH subgroup expressed by the leukemia cells of 108 patients with B cell chronic lymphocytic leukemia (CLL). Surprisingly, we found that six samples (5%) each expressed Ig of more than one VH subgroup. Southern blot analysis demonstrated that these samples each had rearrangements involving both Ig heavy chain alleles. Nucleic acid sequence analyses of the Ig cDNA revealed each to express two functional Ig VH genes: VH3-33 and VH4-39; VH3-7 and VH4-39; VH3-23 and VH4-61; VH2-70 and VH3-30.3; or VH3-30 and VH4-b (DP67). One sample expressed three Ig VH genes: VH2-70, VH3-7, and VH4-59. Despite having more than one Ig heavy chain transcript, each sample was found to express only one functional Ig light chain. From the primary sequence, we deduced that the Ig of some of these CLL samples should react with Lc1, a monoclonal antibody (mAb) reactive with a supratypic cross-reactive idiotype present on Ig encoded by a subgroup of Ig VH4 genes (namely, VH4-39, VH4-b [DP-67], VH4-59, or VH4-61), and B6, an mAb that reacts with Ig encoded by certain Ig VH3 genes (namely, VH3-23, VH3-30, or VH3-30.3), and/or modified staphylococcal protein A (SpA), a 45-kilodalton bacterial "superantigen" that reacts with most Ig of the VH3 subgroup. Flow cytometric analyses revealed that such samples did in fact react with Lc1 and B6 and/or SpA, but not with control mAbs of irrelevant specificity. This study demonstrates that a subset of CLL patients have leukemic B cells that express more than one functional Ig heavy chain.

Address correspondence to Thomas J. Kipps, Division of Hematology/Oncology, Department of Medicine, University of California at San Diego, 9500 Gillman Dr., La Jolla, CA 92093-0663.

We are thankful to Dr. Gregg J. Silverman for the modified SpA used in this study and for his helpful comments. The authors also are grateful to Esther D. Avery and Todd A. Johnson for their assistance in this study.

1 Abbreviations used in this paper: anti-hu, anti-human; CDR, complementarity determining region; CLL, chronic lymphocytic leukemia; CRI, cross-reactive idiotype; MFIR, mean fluorescence intensity ratio; R, replacement mutation; RT, reverse transcriptase; S, silent mutation; SpA, staphylococcal protein A.


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