Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins

Abstract

We examined the immunoglobulin (Ig) heavy chain variable region genes (V H genes) used by leukemia cells of 1220 unrelated patients with chronic lymphocytic leukemia (CLL). We found 1188 (97%) expressed Ig encoded by a single Ig V H subgroup, the most common of which was V H 3 (571 or 48.1%), followed by V H 1 (319 or 26.8%) and V H 4 (241 or 20.2%). Using allele-specific primers, we found 13.8% of all samples (n ‫؍‬ 164) used one major V H 1-69 allele, designated 51p1, 163 of which were not somatically mutated. For these cases, there was marked restriction in the structure of the Ig third complementarity determining regions (CDR3s), which were encoded by a small number of unmutated D and J H gene segments. Strik IntroductionThe mutational status of the immunoglobulin (Ig) genes expressed in B-cell chronic lymphocytic leukemia (CLL) can be used to segregate patients into 2 subsets that have significantly different tendencies for disease progression. Those patients with leukemia cells that express unmutated Ig heavy chain variable region genes (V H genes) have a greater tendency for disease progression and shorter survival than those who have leukemia cells that express Ig V H genes with less than 98% nucleic acid sequence homology with their germ-line counterparts. 1-7 Generally, the Ig V H genes expressed by any leukemia cell population do not display significant intraclonal diversity or tendency to accumulate additional somatic mutations over time. 8 As such, the leukemia cells that express mutated Ig genes apparently do not evolve from cases that originally expressed unmutated Ig genes. Because of this, the presence or absence of Ig somatic mutations was thought by some to reflect 2 subtypes of CLL, each with distinctive cytogenesis. 1,2,9 The subtype that expressed unmutated Ig V H genes was considered to be derived from naive or pre-germinal center B cells, whereas the CLL cells expressing mutated receptors were thought likely to be derived from a post-germinal center or "memory-type" B cells. 10 However, molecular analyses of the Ig V H genes expressed by CLL B cells suggest that neither subtype is derived from a naive, nonselected B cell. CLL B cells express an Ig repertoire that appears more restricted than that of adult blood B cells. Several genes, such as the 51p1 allele of V H 1-69, are expressed at high frequency, 11 are rarely mutated, 12 and constitute a large proportion (eg, Ϸ 20%) of the cases that lack Ig somatic mutation. In addition, prior studies found that 51p1-expressing CLL B cells preferentially use certain diversity (D) and J H gene segments with restricted reading frames (RFs), encoding relatively long third complementarity determining regions (CDR3s) with conserved amino acid motifs. 12 The CDR3s of 51p1-expressing CLL B cells contrasted with those of the Ig heavy chains expressed by CLL B cells that used other Ig V H 1 genes or by nonneoplastic tonsillar or blood B cells that used 51p1. [12][13][14] As the CDR3 is the most variable region of the heavy chain and is directly involved ...

The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia

“…There is growing evidence that a significant proportion of patients with CLL who have unmutated IgV H genes have almost identical antigen receptors, suggesting that their malignant cells are selected by specific antigens. 33,34 It is possible that patients with these ''antigen-driven'' diseases have a reduced ability to develop immune responses against different bacterial or viral antigens. Alternatively, the IgV H mutation status simply may reflect the degree of disease aggressiveness and immune deficiency.…”

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

“…[15][16][17][18][19][20][21][22] Sequence data were analyzed using the ImMunoGeneTics database (http://imgt.cines.fr). 30,31 Sequences with a germline identity X98% were considered as unmutated, and those with an identity o98% were considered as mutated.…”

“…[8][9][10] A rise in IGHV4-34 Abs is also observed in the serum of otherwise healthy individuals in response to acute infections with herpesviruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and in acute Mycoplasma pneumoniae infections. [10][11][12][13] The immunoglobulin gene repertoire expressed by chronic lymphocytic leukemia (CLL) malignant B cells is biased and notable for the existence of subsets with quasi-identical (stereotyped) B-cell receptors (BCRs), [14][15][16][17][18][19][20][21][22][23][24] implying the recognition of structurally similar epitopes, likely selecting the leukemic clones. However, the nature of the selecting antigens and their interactions with CLL progenitors or the malignant cells themselves remain shadowy.…”

Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

“…2,[5][6][7][8][9][10][11] Lately, small subsets of V H 1-69 ϩ cases with more or less identical heavy-and light-chain Ig rearrangement features have also been reported. 12,13 These findings have led to the speculation that unknown antigens could be involved in the pathogenesis of V H 1-69 ϩ B-CLL.…”