Peripheral blood mononuclear cells from five patients with IgG+ B-type chronic lymphocytic leukemia (B-CLL) were analyzed for the presence of clone-specific Ig H chain variable region gene mRNA transcripts linked to C mu and/or C alpha. This was assessed by (1) comparing the lengths of portions of the VHDJH of the IgG+ CLL clones with those of the mu and alpha isotype-expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the mu and alpha isotype-expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with C gamma-specific primers and then amplified by polymerase chain reaction, dominant cDNA were found with lengths corresponding to those of the IgG+ CLL B cell. In addition, in four cases, cDNA of lengths identical to those of the CLL B cell were detected when mRNA was reverse transcribed and amplified using c mu- and/or C alpha-specific primers, strongly suggesting clonal relatedness. These CLL-related mu- and alpha- expressing cDNA were present in greater amounts that unrelated (non- CLL) mu- and alpha-expressing cDNA from normal B cells that used genes of the same VH family. When the sequences of these CLL-related C mu- and C alpha-expressing cDNA were compared with those of the IgG+ CLL clones, it was clear that they were derived from the same ancestral gene as the IgG-expressing CLL B cell, thus documenting their common origin. Finally, nucleotide point mutations were observed in the mu- and alpha-expressing cDNA of certain patients, indicating divergence with the CLL. These data suggest that IgM+ B cells, which are precursors of the leukemic B cells, exist in increased numbers in the blood of most patients with IgG+ B-CELL and that these cells may differentiate, accumulate V genes mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.
ARTICLES|
February 15, 1996
Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification
M Dono,
M Dono
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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S Hashimoto,
S Hashimoto
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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F Fais,
F Fais
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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V Trejo,
V Trejo
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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SL Allen,
SL Allen
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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SM Lichtman,
SM Lichtman
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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P Schulman,
P Schulman
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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VP Vinciguerra,
VP Vinciguerra
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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B Sellars,
B Sellars
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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PK Gregersen,
PK Gregersen
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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M Ferrarini,
M Ferrarini
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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N Chiorazzi
N Chiorazzi
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.
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Blood (1996) 87 (4): 1586–1594.
Citation
M Dono, S Hashimoto, F Fais, V Trejo, SL Allen, SM Lichtman, P Schulman, VP Vinciguerra, B Sellars, PK Gregersen, M Ferrarini, N Chiorazzi; Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification. Blood 1996; 87 (4): 1586–1594. doi: https://doi.org/10.1182/blood.V87.4.1586.bloodjournal8741586
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