Shelterin genes, germ line mutations and chronic lymphocytic leukemia

2017 ◽  
Vol 6 (S1) ◽  
pp. S68-S71 ◽  
Author(s):  
Irma Slavutsky
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Germ Line Mutations

scholarly journals Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Blood ◽  
2016 ◽  
Vol 128 (19) ◽  
pp. 2319-2326 ◽  
Author(s):  
Helen E. Speedy ◽  
Ben Kinnersley ◽  
Daniel Chubb ◽  
Peter Broderick ◽  
Philip J. Law ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Loss Of Function ◽  
Shelterin Complex ◽  
Key Points ◽  
Germ Line Mutations ◽  
Line Loss

Key Points Germ line loss-of-function mutations in shelterin genes occur in a subset of families with CLL. Telomere dysregulation is further implicated in CLL predisposition.

ATM mutations are rare in familial chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 603-609 ◽  
Author(s):  
Martin R. Yuille ◽  
Alison Condie ◽  
Chantelle D. Hudson ◽  
Paul S. Bradshaw ◽  
Elaine M. Stone ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Ataxia Telangiectasia ◽  
Genetic Basis ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Missense Mutations ◽  
Familial Clustering ◽  
Germ Line Mutations ◽  
Atm Gene ◽  
Cell Chronic Lymphocytic Leukemia

Abstract It is now recognized that a subset of B-cell chronic lymphocytic leukemia (CLL) is familial. The genetic basis of familial CLL is poorly understood, but recently germ line mutations in the Ataxia Telangiectasia (ATM) gene have been proposed to confer susceptibility to CLL. The evidence for this notion is, however, not unequivocal. To examine this proposition further we have screened the ATM gene for mutations in CLLs from 61 individuals in 29 families. Truncating ATM mutations, including a knownATM mutation, were detected in 2 affected individuals, but the mutations did not cosegregate with CLL in the families. In addition, 3 novel ATM missense mutations were detected. Common ATM missense mutations were not overrepresented. The data support previous observations that ATM mutation is associated with B-CLL. However, ATM mutations do not account for familial clustering of the disease.

scholarly journals Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

2001 ◽  
Vol 194 (11) ◽  
pp. 1639-1648 ◽  
Author(s):  
Andreas Rosenwald ◽  
Ash A. Alizadeh ◽  
George Widhopf ◽  
Richard Simon ◽  
R. Eric Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Gene Expression Signature ◽  
Lymphocytic Leukemia ◽  
Common Mechanism ◽  
Human Leukemia ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1524-1533 ◽  
Author(s):  
Fiona Murray ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Gerard Tobin ◽  
Myriam Boudjogra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Distinctive Features ◽  
Ighv Gene ◽  
Gene Usage

Abstract Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

scholarly journals Rearrangement and expression of T cell antigen receptor genes in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 178-185
Author(s):  
JD Norton ◽  
J Pattinson ◽  
AV Hoffbrand ◽  
H Jani ◽  
JC Yaxley ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Gene Transcript ◽  
Prolymphocytic Leukemia ◽  
Beta 2 ◽  
Beta Gene ◽  
Cell Chronic Lymphocytic Leukemia

Fifty-nine patients with B cell chronic lymphocytic leukemia (B-CLL) were screened for clonal rearrangement of T cell receptor (TCR) beta and gamma chain genes. Four were found with rearranged TCR beta genes, but none had detectable rearrangement of TCR gamma genes. One typical patient with B-CLL had a TCR beta gene structure consistent with a variable-diversity-joining rearrangement into the C beta 2 gene on one allele. An apparently identical rearrangement pattern was seen in a second patient, which suggested that there may be a restriction on the repertoire of possible TCR beta gene recombinations in mature B cells. Two further patients had a simple deletion of sequences, consistent with a diversity-joining rearrangement into C beta 2 on one allele. All four patients had rearrangements of immunoglobulin heavy- and light- chain genes typical of mature B cell malignancies. However, on review of clinical, morphological, and immunophenotype data, two had features consistent with B cell prolymphocytic leukemia or B lymphoma, and a third had progressed to a prolymphocytic transformation. Low-level expression of a predominantly 1.0- to 1.2-kilobase germ line TCR beta gene transcript was detected in several B-CLLs and at a comparable level in the four with rearranged TCR beta genes. This, together with the low frequency of TCR gene rearrangement, suggests that most B-CLL cases arise at a developmental stage when factors required for TCR gene activity are not operative.

The pattern and distribution of immunoglobulin VH gene mutations in chronic lymphocytic leukemia B cells are consistent with the canonical somatic hypermutation process

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3490-3495 ◽  
Author(s):  
Bradley T. Messmer ◽  
Emilia Albesiano ◽  
Davorka Messmer ◽  
Nicholas Chiorazzi
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Gene Mutations ◽  
Lymphocytic Leukemia ◽  
Antigen Receptors ◽  
Region Gene ◽  
Wobble Position ◽  
Gene Usage ◽  
Vh Gene

Abstract The overexpanded clone in most B-cell-type chronic lymphocytic leukemia (BCLL) patients expresses an immunoglobulin (Ig) heavy chain variable (VH) region gene with some level of mutation. While it is presumed that these mutations were introduced in the progenitor cell of the leukemic clone by the canonical somatic hypermutation (SHM) process, direct evidence of such is lacking. Nucleotide sequences of the Ig VH genes from 172 B-CLL patients were analyzed. Previously described VH gene usage biases were noted. As with canonical SHM, mutations found in B-CLL were more frequent in RGYW hot spots (mutations in an RGYW motif = 44.1%; germ line frequency of RGYW motifs = 25.6%) and favored transitions over transversions (transition-transversion ratio = 1.29). Significantly, transition preference was also noted when only mutations in the wobble position of degenerate codons were considered. Wobble positions are inherently unselected since regardless of change an identical amino acid is encoded; therefore, they represent a window into the nucleotide bias of the mutational mechanism. B-CLL VH mutations concentrated in complementarity-determining region 1 (CDR1) and CDR2, which exhibited higher replacement-to-silent ratios (CDR R/S, 4.60; framework region [FR] R/S, 1.72). These results are consistent with the notion that VH mutations in B-CLL cells result from canonical SHM and select for altered, structurally sound antigen receptors. (Blood. 2004;103:3490-3495)

scholarly journals Rearrangement and expression of T cell antigen receptor genes in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 178-185 ◽  
Author(s):  
JD Norton ◽  
J Pattinson ◽  
AV Hoffbrand ◽  
H Jani ◽  
JC Yaxley ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Gene Transcript ◽  
Prolymphocytic Leukemia ◽  
Beta 2 ◽  
Beta Gene ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Fifty-nine patients with B cell chronic lymphocytic leukemia (B-CLL) were screened for clonal rearrangement of T cell receptor (TCR) beta and gamma chain genes. Four were found with rearranged TCR beta genes, but none had detectable rearrangement of TCR gamma genes. One typical patient with B-CLL had a TCR beta gene structure consistent with a variable-diversity-joining rearrangement into the C beta 2 gene on one allele. An apparently identical rearrangement pattern was seen in a second patient, which suggested that there may be a restriction on the repertoire of possible TCR beta gene recombinations in mature B cells. Two further patients had a simple deletion of sequences, consistent with a diversity-joining rearrangement into C beta 2 on one allele. All four patients had rearrangements of immunoglobulin heavy- and light- chain genes typical of mature B cell malignancies. However, on review of clinical, morphological, and immunophenotype data, two had features consistent with B cell prolymphocytic leukemia or B lymphoma, and a third had progressed to a prolymphocytic transformation. Low-level expression of a predominantly 1.0- to 1.2-kilobase germ line TCR beta gene transcript was detected in several B-CLLs and at a comparable level in the four with rearranged TCR beta genes. This, together with the low frequency of TCR gene rearrangement, suggests that most B-CLL cases arise at a developmental stage when factors required for TCR gene activity are not operative.

Somatic ATM Mutations Indicate a Pathogenic Role of ATM in B-Cell Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 748-753 ◽  
Author(s):  
Claudia Schaffner ◽  
Stephan Stilgenbauer ◽  
Gudrun A. Rappold ◽  
Hartmut Döhner ◽  
Peter Lichter
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Point Mutation ◽  
Mutation Analysis ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Pathogenic Role ◽  
Atm Gene ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Deletion in chromosome bands 11q22-q23 is one of the most common chromosome aberrations in B-cell chronic lymphocytic leukemia (B-CLL). It is associated with extensive lymph node involvement and poor survival. The minimal consensus deletion comprises a segment, which contains the ATM gene presenting an interesting candidate gene, as mutations in ATM predispose A-T patients to lymphoid malignancies. To investigate a potential pathogenic role of ATM in B-cell tumorigenesis, we performed mutation analysis of ATM in 29 malignant lymphomas of B-cell origin (B-CLL = 27; mantle cell lymphoma, [MCL] = 2). Twenty-three of these carried an 11q22-q23 deletion. In five B-CLLs and one MCL with deletion of one ATMallele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, alteration, or truncation of the protein. In addition, mutation analysis identified point mutations in three cases without 11q deletion: two B-CLLs with one altered allele and one MCL with both alleles mutated. In four cases analyzed, theATM alterations were not present in the germ line indicating a somatic origin of the mutations. Our study demonstrates somatic disruption of both alleles of the ATM gene by deletion or point mutation and thus its pathogenic role in sporadic B-cell lineage tumors.

Shorter Telomeres Are Associated with the Unfavourable Chromosomal Aberrations Del 17p and Del 11q in Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3131-3131
Author(s):  
Ludger Sellmann ◽  
Dirk de Beer ◽  
Marius Bartels ◽  
Holger Nueckel ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Chromosomal Aberrations ◽  
Germ Line ◽  
Average Length ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Snp Chip ◽  
Mutational Status

Abstract BACKGROUND: In chronic lymphocytic leukemia (CLL) short telomeres were shown to be associated with mutational status, progression free survival (PFS) and overall survival (Damle et al., 2004). Chromosomal instability increases with shortening of telomeres. Recently, a relationship between telomere length and number of chromosomal aberrations has been shown if telomere length was investigated by quantitative real-time polymerase chain reaction (Tel-PCR) (Roos et al., 2008). The aim of the present study was to correlate average telomere length of individual cells measured by multicolor flow-FISH to established prognostic factors and genomic aberrations. PATIENTS and METHODS: Blood samples from 64 patients with CLL were analyzed. Flow cytometry was performed for quantification of ZAP-70 and CD 38 expression with a cut off at 20%. Immunoglobulin variable heavy chain (IGVH) genes were sequenced. An IGVH gene sequence with less than 98% homology with the corresponding germ-line sequence was considered to be mutated. Chromosomal alterations were investigated by fluorescence in situ hybridization (FISH) with the following gene probes: LSI 13q14, LSI 13q34, CEP 12, LSI 17p13, LSI 11q22–23. Copy number changes were also detected in 18 samples by SNP-chip analysis. The average length of telomere repeats at chromosome ends was measured by multicolor flow-FISH. Values of telomere length from CLL cells were correlated to values of telomere lengths of B lymphocytes from healthy age matched individuals (delta telomere length=Δtel). RESULTS: The average telomere length of the clonal B-cells was short. Patient samples from advanced Binet stages (B/C) had significantly shorter telomeres (Δtel −4.8 ± 1.0 kb) than patients samples from Binet A (Δtel −3.4 ± 1.2 kb, p=0.03). The average telomere length was significantly shorter for ZAP-70+ (Δtel −5.0 ± 0.5 kb) and CD38+ (Δtel −4.9 ± 0.7 kb) patient samples than for ZAP-70− (Δtel −2.4 ± 0.8 kb) and CD38− (Δtel −3.0 ± 1.0 kb) patient samples, respectively (p<0.005, p<0.005). IGVH unmutated CLL samples exhibited significant shorter telomere lengths (Δtel −4.8 ± 0.4 kb) than mutated samples (Δtel −2.8 ± 0.9 kb, p<0.005). Interestingly CLL samples harbouring del 17p and del 11q had significantly shorter average telomere length (Δtel −5.3 ± 0.2 kb, n= 8) than samples without these aberrations (Δtel −4.0 ± 1.2 kb; n= 56, p<0.005). Furthermore we found a tendency of an increase in the number of chromosomal aberrations detected by SNP-chip with shorter telomeres. DISCUSSION: We are able to confirm significant shorter telomeres in CLL samples with unfavourable prognostic factors like advanced Binet stage, positivity for ZAP-70 or CD38 and unmutated IGVH genes compared to their favourable counterparts. CLL samples with the chromosomal aberrations del 17p and del 11q are associated with bad clinical outcome. CLL with these aberrations of the present study demonstrated significantly shorter telomeres compared to cases without these abnormalities. Additional studies relating impact of telomere length on genomic instability detected by SNP-chip are ongoing.

Monoclonal B-Cell Lymphocytosis Is Commonly Observed Among Unaffected Members of High Risk CLL Families.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1232-1232 ◽  
Author(s):  
Lynn R Goldin ◽  
Mark C Lanasa ◽  
Susan L Slager ◽  
Sara S Strom ◽  
Nicola J Camp ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Detection Sensitivity ◽  
Flow Cytometry Analysis ◽  
First Degree Relatives ◽  
High Risk Families

Abstract Abstract 1232 Poster Board I-254 B-Chronic Lymphocytic Leukemia (CLL) shows a strong familial risk and also co-aggregates with other indolent lymphomas. Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition characterized by small B-cell clones, most with a surface phenotype similar to that of chronic lymphocytic leukemia (CLL). These clones are detectable at low absolute lymphocyte cell (ALC) numbers in otherwise healthy individuals using sensitive 6 or 8 color flow cytometry analysis and can be a precursor to CLL. In the general population, MBL increases with age with a prevalence of 5% in individuals over age 65. In contrast, the rate of MBL is 13-18% in first degree relatives of CLL patients in high risk families. In the largest study to date, we report the characteristics of MBL among 430 first-degree relatives of CLL patients (with no associated lymphoproliferative diseases [LPD]) in 132 high risk families. Patients and Methods Individuals studied came from “high risk” families (defined as those with two or more confirmed cases of CLL) that are participating in the Genetic Epidemiology of CLL Consortium. Multi-parameter flow cytometry analysis with a detection sensitivity of 0.02% was performed on either fresh or cryopreserved PBMC and MBL was classified according to previously published criteria (Marti et al, Br. J Haematol 130:325, 2005). Both the ALC and the absolute B cell count (B-ALC) were calculated for each individual. Survival analysis was used to compute the probability of developing MBL with age using the life table method. Results The overall rate of MBL was 17% (73/430) among first–degree relatives but the probability for developing MBL by age 90 was 51%. Males had a slightly higher (but non-significant) risk for MBL than females. MBL patients had significantly higher ALC and B-ALC than did those with normal immunophenotype. The mean ALC was 2.5×109/L among MBL patients, and 20% had an ALC greater than 3 ×109/L. The B-ALC count averaged 0.51 ×109/L. Ninety percent of the MBL cases had a CLL-like phenotype (CD20dim, CD5+, CD23+). Conclusions MBL is found at a very high rate in families selected for having 2 or more patients with CLL suggesting that MBL reflects inherited predisposition to CLL. Although most of the MBL cases in these families had low cell counts and thus have a presumed low likelihood of progressing to CLL or other LPD, a higher proportion of them had lymphocytosis compared to those with normal immunophenotype. We hypothesize that if MBL is an early step in the process of development of CLL, then germ line genes are likely to be acting early in carcinogenesis with more “hits” required before CLL develops. By looking for genes associated with MBL or CLL in families or in the population, we could substantially increase our power to identify germ line genes predisposing to CLL. Disclosures Kay: Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees; Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding.

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