Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification - PubMed (original) (raw)

Comparative Study

. 2002 Sep 2;196(5):629-39.

doi: 10.1084/jem.20011693.

Peter McGuire, Hong Zan, Xiao-Jie Yan, Andrea Cerutti, Emilia Albesiano, Steven L Allen, Vincent Vinciguerra, Kanti R Rai, Manlio Ferrarini, Paolo Casali, Nicholas Chiorazzi

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Comparative Study

Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification

Carmela Gurrieri et al. J Exp Med. 2002.

Abstract

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5(+) B lymphocyte that is thought not to undergo intraclonal diversification. Using V(H)DJ(H) cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1-35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V(H)DJ(H) genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.

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Figures

Figure 1.

Figure 1.

SSCP analysis from two CLL cases displaying either the absence or presence of intraclonal diversification. All 27 VHDJH transcripts from CLL 216 showed identical mobility (A). In CLL 105, seven of the 25 VHDJH transcripts showed a mobility pattern different from that displayed by the remaining 18 VHDJH transcripts (B). Sequence analysis showed that the VHDJH cDNAs 1–3 were all collinear and collinear with the most represented transcripts confirming their monoclonality. However, these transcripts displayed nucleotide variations distributed randomly throughout the VH segment. VHDJH transcripts labeled 1 were identical among themselves but different, though collinear, from the VHDJH transcripts 2 and 3, and the most represented transcripts. VHDJH transcripts 2 were all identical but different, though collinear, from the VHDJH transcripts 1, 3, and the most represented transcripts. VHDJH transcripts 3 were identical but different, though collinear, from the VHDJH transcripts 1, 2 and the most represented transcripts.

Figure 2.

Figure 2.

Genealogical tree constructed using VHDJH sequences of CLL nos. 261 and 105. Point-mutations are indicated by their codon number and the nature of the base change. Shared point-mutations and acquired unique point-mutations are indicated above and below the line, respectively. Vertical bars depict S mutations, and lollipops depict R mutations. The putative intermediate elements are depicted with gray nuclei.

Figure 3.

Figure 3.

Schematic representation of the steps involved in the in vitro induction of somatic hypermutation in CLL B cells.

Figure 4.

Figure 4.

In vitro induction of somatic hypermutation. CLL 136 and CLL 216 did not exhibit evidence of in vivo intraclonal diversity (see Table I). After in vitro stimulation, 3 of 32 VHDJH transcripts in CLL 136 and 5 of 34 in CLL 216 displayed gel mobilities different from that of corresponding transcripts obtained from the unstimulated CLL cells. Transcripts were sequenced and each contained at least one nucleotide change.

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