Somatic mutation of bcl-6 genes can occur in the absence of VH mutations in chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3534-3540 ◽  
Author(s):  
Surinder S. Sahota ◽  
Zadie Davis ◽  
Terry J. Hamblin ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
V Genes ◽  
History Of ◽  
Vh Genes ◽  
V Region

Abstract Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated VH genes consistent with a naive B cell, and the other with mutated VH genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5′ noncoding region of thebcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in VH and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated VH genes, with 4 of 10 cases clearly showing mutations inbcl-6. In those CLLs defined by somatically mutated VH genes, 4 of 9 cases predictively showed bcl-6mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of VH genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the VH and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.

Somatic mutation of bcl-6 genes can occur in the absence of VH mutations in chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3534-3540 ◽  
Author(s):  
Surinder S. Sahota ◽  
Zadie Davis ◽  
Terry J. Hamblin ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
V Genes ◽  
History Of ◽  
Vh Genes ◽  
V Region

Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated VH genes consistent with a naive B cell, and the other with mutated VH genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5′ noncoding region of thebcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in VH and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated VH genes, with 4 of 10 cases clearly showing mutations inbcl-6. In those CLLs defined by somatically mutated VH genes, 4 of 9 cases predictively showed bcl-6mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of VH genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the VH and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.

Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1848-1854 ◽  
Author(s):  
Terry J. Hamblin ◽  
Zadie Davis ◽  
Anne Gardiner ◽  
David G. Oscier ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Trisomy 12 ◽  
Vh Gene ◽  
Vh Genes ◽  
Variable Region Genes

Abstract Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.

scholarly journals Differential Rates of Somatic Hypermutation in VH Genes Among Subsets of Chronic Lymphocytic Leukemia Defined by Chromosomal Abnormalities

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4153-4160 ◽  
Author(s):  
David G. Oscier ◽  
Andrew Thompsett ◽  
Delin Zhu ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Mutation ◽  
Chromosomal Abnormalities ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Karyotypic Abnormality ◽  
Trisomy 12 ◽  
History Of ◽  
Vh Genes

Abstract Chronic lymphocytic leukemia (CLL) is a B-cell tumor involving small lymphocytes that generally express the CD5 antigen and low levels of surface Ig. Within this definition, there is heterogeneity among cases in cell morphology, karyotypic abnormalities, and clinical course. Trisomy 12, the most frequent karyotypic abnormality, is commonly found in a subset of CLL with atypical morphology. It has also been associated with advanced disease, and possibly with a less favorable prognosis. A further subset of cases with abnormalities involving chromosome 13q14 have typical lymphocyte morphology. Occasionally, the two abnormalities are found together. To assess the clonal history of the cell of origin in disease subsets defined by these two chromosomal abnormalities, we investigated the usage of VH genes and the pattern of somatic mutation in 10 cases of trisomy 12 with atypical morphology and eight cases of 13q14 abnormality with typical morphology. In addition, four cases with both chromosomal abnormalities were analyzed. Results confirm a common usage of the VH1 family in all subsets. However, the patterns of somatic mutation were distinct, with cases of trisomy 12 showing a minimal level of mutation (mean ± SD, 0.34% ± 0.86%) and cases of 13q14 abnormality showing significant levels (6.5% ± 1.67%). The four cases with both abnormalities showed a mixed pattern. All mutated cases had intraclonal homogeneity, and three of 10 had a pattern indicative of antigen selection. These results suggest that the clonal history of the two subsets of CLL may differ.

Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1848-1854 ◽  
Author(s):  
Terry J. Hamblin ◽  
Zadie Davis ◽  
Anne Gardiner ◽  
David G. Oscier ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Trisomy 12 ◽  
Vh Gene ◽  
Vh Genes ◽  
Variable Region Genes

Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

Gene Mutation Signature and Its Pathogenesis Role in Chronic Lymphocytic Leukemia in China: Different from the Western Reports

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4360-4360
Author(s):  
Shuhua Yi ◽  
Xiong Wenjie ◽  
Li Heng ◽  
Zhen Yu ◽  
Zengjun Li ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Gene Mutation ◽  
Germinal Center ◽  
Recurrent Mutation ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Mutation Status ◽  
Western Population ◽  
Germinal Center B Cell

Abstract Background Recently, the molecular aberration of chronic lymphocytic leukemia (CLL) has been widely investigated in the Western population. Genes mutation detecting by next generation sequencing (NGS) provided a fair-new view to explain the pathogenesis of CLL and guide the clinical practices. Limited primary data indicated the mutation signature of CLL in China might be different from the Western reports, which deserved further systematical investigation. Methods A panel with 76 genes was designed to identify mutation status by NGS in 129 CLL patients. This 76 genes panel had been reported as recurrent mutation in CLL and other lymphoproliferative disorders. Whole exomes of each gene were sequenced with a mean read depth of 1957 and a coverage of target region of 99.6%. Results We finally revealed the presence of recurrent mutations (n ≥ 2) in 63 genes. The most frequency of mutational genes were as follow: FAT1, 35 cases (27.1%); KMT2D/MLL2, 29 cases (22.5%); TP53, 26 cases (20.2%); FAT4 24 cases (18.6%); NOTCH1, 22 cases (17.1%); ATM, 19 cases (14.7%); FBXW7, 16 cases (12.4%); SPEN, 16 cases (12.4%); BRAF, 15 cases (11.6%); MYD88 14 cases (10.9%); SF3B1, 14 cases (10.9%); APC, 13 cases (10.1%); CREBBP 13 cases (10.1%); TET2, 13 cases (10.1%); POT1, 11 cases (8.5%); EP300, 10 cases (7.8%); KMT2B, 10 cases (7.8%); MAP3K14, 10 cases (7.8%); TCF3, 10 cases (7.8%); NOTCH2, 9 cases (7.0%); KLF2, 8 cases (6.2%); SMARCA4, 8 cases (6.2%); BIRC3, 7 cases (5.4%); EGR2, 7 cases (5.4%); KLHL31, 7 cases (5.4%); KLHL6, 7 cases (5.4%), et al. We compared the mutated sites of each gene in this study with other established studies, and found that the mutation sites distribution of each recurrent mutated gene were comparable to the well-known mutated sites, which indicated the similar function change. Then, we classified these recurrent mutation genes into different signaling pathway, according to their affected function. We found that chromatin modification pathway was the most affected pathway, accounting for 74 patients (57.4%), followed by NF-κB pathway (58 patients, 45.0%), NOTHC1 pathway (52 patients, 40.3%), Hippo pathway (50 patients, 38.8%), DNA damage pathway (48 patients, 37.2%), Wnt/β-catenin pathway (31 patients, 24.0%) and post-transcriptional modification (19 patients, 14.7%). The IGHV mutation rate in the 115 patients was 67.0%, which was significantly higher than the Western reports. In aspect of prognostic role of these mutation genes, IGHV mutation status, the TP53 abnormality (deletion and mutation) and mutated EGFR impacted both PFS and OS independently, while mutated FAT1 was additional independent prognostic factor for PFS and mutated POT1 and KLF2 were another two independent factors for OS. IGHV mutation status and mutated TRAF2 were both independent factors for TTT. Integrating the function of these high frequency mutated genes, high proportion of IGHV gene mutation and cell-of-origin of CLL model initiated recently, these prevalent mutation genes in this study were supposed to precipitate the pathogenesis of CLL from the initial tumor stem cell to germinal center B cell. Conclusion The gene mutation signature of CLL in China is different from the Western population, which may skew the cell-of-origin of CLL in China towards the germinal center B cell maturation route, other than other maturation way, such as marginal zone B cell origin. Disclosures No relevant conflicts of interest to declare.

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

1993 ◽  
Vol 177 (4) ◽  
pp. 1039-1046 ◽  
Author(s):  
L Z Rassenti ◽  
T J Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Sequence Homology ◽  
Common Property ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
V Genes ◽  
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.

Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2562-2568 ◽  
Author(s):  
Delin Zhu ◽  
Helen McCarthy ◽  
Christian H. Ottensmeier ◽  
Peter Johnson ◽  
Terry J. Hamblin ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Single Chain ◽  
Single Chain Fv ◽  
Glycosylation Sites ◽  
Vh Genes

Most patients with follicular lymphoma (FL) have somatically mutated V genes with intraclonal variation, consistent with location in the germinal center site. Using our own and published sequences, we have investigated the frequency of potential N-glycosylation sites introduced into functional VH genes as a consequence of somatic mutation. FL cells were compared with normal memory B cells or plasma cells matched for similar levels of mutation. Strikingly, novel sites were detected in 55 of 70 (79%) patients with FL, compared to 7 of 75 (9%) in the normal B-cell population (P < .001). Diffuse large B-cell lymphoma (DLCL) showed an intermediate frequency (13 of 32 [41%] patients). Myeloma and the mutated subset of chronic lymphocytic leukemia showed frequencies similar to those of normal cells in 5 of 64 (8%) patients and 5 of 40 (13%) patients, respectively. In 3 of 3 random patients with FL, immunoglobulin was expressed as recombinant single-chain Fv inPichia pastoris, and glycosylation was demonstrated. These findings indicate that N-glycosylation of the variable region may be common in FL and in a subset of DLCL. Most novel sites are located in the complementarity-determining regions. VH sequences of nonfunctional VH genes contained few sites, arguing for positive selection in FL. One possibility is that the added carbohydrate in the variable region contributes to interaction with elements in the germinal center environment. This common feature of FL may be critical for tumor behavior.

Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 660-669 ◽  
Author(s):  
Maria Teresa Sabrina Bertilaccio ◽  
Giorgia Simonetti ◽  
Antonis Dagklis ◽  
Martina Rocchi ◽  
Tania Veliz Rodriguez ◽  
...  
Keyword(s):  
Immune Response ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Adaptive Immune Response ◽  
Lymphocytic Leukemia ◽  
Fine Tuning ◽  
Terminal Phase ◽  
Lymphoid Malignancies ◽  
History Of ◽  
Molecular Patterns

Abstract Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R–like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed Eμ-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression.

Hodgkin and Reed-Sternberg–like cells in B-cell chronic lymphocytic leukemia represent the outgrowth of single germinal-center B-cell–derived clones: potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 1023-1031 ◽  
Author(s):  
Holger Kanzler ◽  
Ralf Küppers ◽  
Sabine Helmes ◽  
Hans-Heinrich Wacker ◽  
Andreas Chott ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Hodgkin’S Disease ◽  
Lymphocytic Leukemia ◽  
Cell Clones ◽  
Germinal Center B Cell ◽  
V Gene ◽  
Cell Chronic Lymphocytic Leukemia

In rare cases of B-cell chronic lymphocytic leukemia (B-CLL), large cells morphologically similar to or indistinguishable from Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin's disease (HD) can be found in a background of otherwise typical B-CLL. To test these HRS-like cells for a potential clonal relationship to the B-CLL cells, single cells were micromanipulated from immunostained tissue sections, and rearranged immunoglobulin genes were amplified from HRS-like cells and B-CLL cells and sequenced. The same variable (V) gene rearrangements with shared and distinct somatic mutations were found in HRS-like and B-CLL cells from 1 patient, which indicates derivation of these cells from 2 distinct members of a germinal-center B-cell clone. Separate clonal Vgene rearrangements were amplified from HRS-like and B-CLL cells from 2 other patients, showing concomitant presence of 2 distinct expanded B-cell clones. Epstein-Barr virus (EBV) was detected in the HRS-like cells of these 2 latter cases, indicating clonal expansion of an EBV-harboring B cell in the setting of B-CLL. There is evidence that HRS-like cells in B-CLL, like HRS cells in HD, derive from germinal-center B cells. In all cases, somatic mutations have been detected in the rearranged V genes of the HRS-like cells, and in 1 of the EBV-positive HRS-like cell clones, somatic mutations rendered an originally functional V gene rearrangement nonfunctional. We speculate that the HRS-like cells in B-CLL represent potential precursors for HRS cells causing HD.

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