Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification

Mariella Dono, Shiori Hashimoto, Franco Fais, Velia Trejo, Steven L. Allen, Stuart M. Lichtman, Philip Schulman, Vincent P. Vinciguerra, Brian Sellars, Peter K. Gregersen, Manlio Ferrarini, Nicholas Chiorazzi

Research output: Contribution to journalArticlepeer-review

Abstract

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 Cμ and/or Cα. This was assessed by (1) comparing the lengths of portions of the V(H)DJ(H) of the IgG+ CLL clones with those of the μ and α isotype- expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the μ and α isotype- expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with Cγ-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 Cμ- and/or Cα-specific primers, strongly suggesting clonal relatedness. These CLL-related μ- and α-expressing cDNA were present in greater amounts than unrelated (non-CLL) μ- and α-expressing cDNA from normal B cells that used genes of the same V(H) family. When the sequences of these CLL-related Cμ- and Cα-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 μ- and α-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-CLL and that these cells may differentiate, accumulate V gene mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.

Original languageEnglish
Pages (from-to)1586-1594
Number of pages9
JournalBlood
Volume87
Issue number4
Publication statusPublished - Feb 15 1996

ASJC Scopus subject areas

  • Hematology

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