Lack of extensive mutations in the VH5 genes used in common B cell chronic lymphocytic leukemia.

B cell chronic lymphocytic leukemia (CLL) is a malignancy of the CD5+ B cells. Prior studies indicated that CLL B cells generally express immunoglobulin (Ig) VH and VL genes with little or no somatic mutations. However, a recent report indicated that VH251, one of three VH genes belonging to the VH5 subgroup (e.g., VH251, VH32, and VH15), not only is frequently rearranged in this disease, but also has extensive and selective mutations when expressed by CLL B cells. The extent and nature of these mutations contrasts markedly from the low level of mutations noted in VH5 genes used by normal B cells or other Ig V genes found expressed in CLL. To determine whether this difference reflects a unique property of VH251 or a previously unrecognized subgroup of CLL, we examined for VH5 Ig gene rearrangements in leukemia cells from 68 patients that satisfied clinical and diagnostic criteria for CD5+ B cell CLL. Southern blot hybridization studies with probes for VH251 and the JH locus revealed that only 7 (10%) of the 68 monoclonal CLL cell populations had undergone Ig gene rearrangement involving VH5 genes. Two (3%) were found to have functionally rearranged VH5 genes that shared > or = 98% sequence homology with 5-2R1, a VH251 gene isolated from a pre-B cell acute lymphocytic leukemia. The other five CLL (7%) had functionally rearranged VH5 genes that each shared > or = 99% nucleic acid sequence homology with a germline VH32 isolated from human sperm DNA. These data indicate that VH251 or VH32 also may be expressed by CD5+ CLL B cells with little or no somatic mutation. These findings contrast with a recently published study on VH5 gene expression in B CLL and contest the hypothesis that extensive somatic mutation is a common property of the VH5 genes used in this disease. Further work to define the clinical and/or phenotypic characteristics of patients with leukemia cells that express mutated versus nonmutated Ig V genes may reveal subsets of CLL that possibly differ in their cytogenesis, etiopathogenesis, and/or clinical behavior.

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Extensive and selective mutation of a rearranged VH5 gene in human B cell chronic lymphocytic leukemia.

Journal of Experimental Medicine ◽

10.1084/jem.176.4.1073 ◽

1992 ◽

Vol 176 (4) ◽

pp. 1073-1081 ◽

Cited By ~ 40

Author(s):

J Cai ◽

C Humphries ◽

A Richardson ◽

P W Tucker

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Somatic Mutation ◽

Lymphocytic Leukemia ◽

Barr Virus ◽

Charge Analysis ◽

Epstein Barr ◽

Cell Chronic Lymphocytic Leukemia ◽

Human B Cell

B cell chronic lymphocytic leukemia (CLL) is the malignant, monoclonal equivalent of a human CD5+ B cell. Previous studies have shown that the VH and VL genes rearranged and/or expressed in CLL have few and apparently random mutations. However, in this study, we have found that the rearranged VH251 gene, one of the three-membered VH5 family, has extensive and selective mutations in B-CLL cells. Somatic mutation at the nucleotide level is 6.03% in B-CLLs whereas the somatic mutation levels are much lower in CD5+ and CD5- cord B cells, adult peripheral blood B cells, and Epstein-Barr virus-transformed CD5+ B cell lines (0.45, 0.93, and 1.92%, respectively). Complementary determining region 1 (CDR1) mutation in CLLs is particularly prevalent, and interchanges in CDRs often lead to acquisition of charge. Analysis of somatic mutations and mutations to charged residues demonstrated that the mutations in CLLs are highly selected.

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2.26 Clopidogrel (Plavix) Induces In Vivo Reduction of Normal B Cells and In Vitro Apoptosis of B-Cell Chronic Lymphocytic Leukemia Cells

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2011.09.059 ◽

2011 ◽

Vol 11 ◽

pp. S175

Author(s):

Alain Berrebi ◽

Gabriel Duek ◽

Lucette Bassous ◽

Mordechai Shtalrid ◽

Lev Shvidel

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Cell Chronic Lymphocytic Leukemia

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A novel monoclonal antibody recognizing human thymocytes and B-cell chronic lymphocytic leukemia cells

Immunology Letters ◽

10.1016/0165-2478(94)90098-1 ◽

1994 ◽

Vol 39 (2) ◽

pp. 137-146 ◽

Cited By ~ 1

Author(s):

P. Tassone ◽

P. Bonelli ◽

F. Tuccillo ◽

H.M. Bond ◽

M.C. Turco ◽

...

Keyword(s):

Monoclonal Antibody ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Cell Chronic Lymphocytic Leukemia

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COMPARISON OF CHROMOSOMAL REARRANGEMENTS IN BONE MARROW CELLS AND BLAST TRANSFORMED B-CELLS IN RELAPSE OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/ SMALL LYMPHOCYTIC LYMPHOMA

Experimental Oncology ◽

10.31768/2312-8852.2017.39(2):141-144 ◽

2017 ◽

Vol 39 (2) ◽

pp. 141-144

Author(s):

S V Andreieva ◽

K V Korets ◽

O E Ruzhinska ◽

I M Skorokhod ◽

O G Alkhimova

Keyword(s):

Bone Marrow ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Chromosomal Rearrangements ◽

Lymphocytic Leukemia ◽

Banding Technique ◽

Small Lymphocytic Lymphoma ◽

Detection Frequency ◽

Cell Chronic Lymphocytic Leukemia

Aim: The genetic mechanisms of resistance to chemotherapy in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) are not clear. We aimed to determine the peculiarities of abnormal karyotype formation in bone marrow (BM) cells and peripheral blood (PB) blast transformed B-cells in relapse of B-CLL/SLL. Materials and Methods: Cytogenetic GTG banding technique and molecular cytogenetic in interphase cells (i-FISH) studies of BM cells and PB blast transformed B-lymphocytes were performed in 14 patients (10 males and 4 females) with B-CLL/SLL. Results: The results of karyotyping BM and PB cells revealed the heterogeneity of cytogenetic abnormalities in combined single nosological group of B-CLL/SLL. In PB B-cells, chromosome abnormalities related to a poor prognosis group were registered 2.5 times more often than in BM cells. Additional near tetraploid clones that occurred in 57.1% cases were the peculiar feature of BM cell karyotypes. Chromosomal rearrangements characteristic of the group of adverse cytogenetic prognosis were revealed in all cases from which in 2 cases by karyotyping BM cells, in 6 cases in PB B-cells and in 8 cases by the i-FISH method in BM cells, i.e. their detection frequency was 3 times higher in PB B-cells and 4 times higher when analyzing by i-FISH in BM cells. Conclusions: Mismatch in abnormal karyotypes in BM and PB B-cells by the presence of quantitative and structural chromosomal rearrangements may be indicative of simultaneous and independent processes of abnormal clone formation in the lymph nodes and BM hematopoietic cells. Accumulation the information about previously unidentified chromosomal rearrangements in relapse of the disease may help to understand the ways of resistance formation to chemotherapy.

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Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v71.4.1012.bloodjournal7141012 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1012-1020 ◽

Cited By ~ 1

Author(s):

JS Moore ◽

MB Prystowsky ◽

RG Hoover ◽

EC Besa ◽

PC Nowell

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Specific Immunoglobulin ◽

Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

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