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In Multiple Myeloma, Circulating Hyperdiploid B Cells Have Clonotypic Immunoglobulin Heavy Chain Rearrangements and May Mediate Spread of Disease¹

Departments of Oncology and Medicine, University of Alberta, Edmonton AB, Canada T6G1Z2

DNA aneuploidy characterizes a proportion of malignant bone marrow (BM)-localized plasma cells in multiple myeloma (MM). This analysis shows that for most MM patients, circulating clonotypic B cells in MM are also hyperdiploid. Although all normal B cells and some malignant B cells are diploid, hyperdiploidy is likely to be exclusive to those that are malignant. Hyperdiploid MM B cells express CD34 and have clonotypic IgH transcripts, confirming them as part of the malignant clone. For MM, 92% (70/76) of patients had a DNA hyperdiploid subset [5–30% of peripheral blood mononuclear cells (PBMCs)] of CD19⁺ B cells. All CD19⁺ PBMCs in MM expressed CD19 and IgH variable diversity joining (VDJ) transcripts, confirming them as B cells. DNA aneuploid cells were undetectable in T or B lymphocytes from normal blood, spleen or thymus, or in blood from patients with B chronic lymphocytic leukemia. In MM, untreated patients had the highest DNA index (1.12). DNA hyperdiploid PBMCs were most frequent among untreated patients and were significantly reduced after chemotherapy. Diploid B cells were significantly more frequent after chemotherapy than at diagnosis. Of the hyperdiploid PBMCs, 81 ± 3% expressed CD34 and CD19. In contrast to circulating CD34⁺ B cells, CD34^- B cells in MM are diploid. In MM, unlike hyperdiploid PBMC B cells, hyperdiploid BM plasma cells lack both CD34 and CD19, suggesting that loss of CD34 correlates with differentiation and BM anchoring. In situ reverse transcription-PCR of the CD34⁺ (hyperdiploid) and CD34^- (diploid) PBMC B-cell subsets was performed using patient-specific primers to amplify clonotypic IgH VDJ transcripts. Confirming previous work, CD34⁺ hyperdiploid MM PBMCs were clonotypic (86 ± 5%). In contrast, CD34^- diploid MM PBMCs had few monoclonal cells (4.8 ± 2%). The lack of hyperdiploidy, together with the relative absence of cells having clonotypic transcripts, suggests these polyclonal CD34^- B cells are normal. After culture in colchicine to arrest mitosis, hyperdiploid B cells were reduced and MM B cells accumulated in a diploid G₂-M, suggesting that hyperdiploid in MM may represent a transient S-phase arrest rather than an aneuploid G₀ phase. The DNA hyperdiploidy of CD34⁺ clonotypic B cells suggests these cells may be clinically important constituents of the myeloma clone and that they may play a direct role in the spread of myeloma.

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