The t(14;19)(q32;q13) Translocation in B Lymphoproliferative Disorders: A Continuum from Chronic Lymphocytic Leukemia (CLL) to Marginal Zone Lymphoma (MZL)?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4944-4944
Author(s):  
Florence Nguyen-Khac ◽  
Elise Chapiro ◽  
Isabelle Radford-Weiss ◽  
Christian Bastard ◽  
Leroux Dominique ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Abnormalities ◽  
B Cell Lymphoma ◽  
Biological Data ◽  
Lymphocytic Leukemia ◽  
Recurrent Event ◽  
Fish Analysis ◽  
Mutational Status ◽  
Independent Analysis ◽  
7Q Deletion

Abstract Translocation t(14;19)(q32;q13) juxtaposing BCL3 in 19q13 with IGH in 14q32, is a rare recurrent event found in patients with B-cell malignancies. So far, a few cases of well-documented B-cell neoplasm have been reported. We analyzed 34 patients with t(14;19) and 1 patient with a variant t(2;19)(p11;q13) collected by the Groupe Francophone de Cytogenetique Hematologique on the basis of cytogenetic abnormality. Clinico-biological data, morphological review, immunophenotyping with Matutes’ score, conventional karyotype and FISH analysis with BCL3, IGH, CEP12, 13q14, ATM, TP53, 6q21 probes, and IgVH mutational status were recorded. The sex ratio was 22M/13F, the median age at diagnosis was 61 [39–89], the lymphocyte count was > 4×109/l in 96% of patients, and spleen enlargement was found in 47%. 31% (11/35) were morphologically classified CLL, 37% (13/35) atypical CLL, 20% (7/35) MZL; 79% had features of disease progression; 3 of the 4 latter were Diffuse Large B Cell Lymphoma, possibly transformed from MZL. 87% were CD5+, 72% had a Matutes’ score < 3. The IgVH genes were unmutated in 9/11 cases. The time to treatment was < 1 year in 68% of patients. The BCL3 locus involvement was confirmed by FISH analysis in all cases. 46% of cases showed complex karyotype. The chromosomal abnormalities associated with t(14;19) were +12 (57%), 6q- (27%), +3 (15%), 11q- (15%), 13q- (13%), 17p- (12%), +18 (12%), 7q- (12%). Comparison with published cytogenetic CLL data shows that deletion 6q was frequent and deletion 13q uncommon. Trisomies 3 and 18, and 7q deletion are less common than in published MZL. The independent analysis of our series of CLL/atypical CLL and MZL gave the same tendency. The chromosomal abnormalities associated with t(14;19) are not specific, but their frequencies are between those of typical CLL and MZL suggesting an intermediary status between the 2 malignancies. The t(14;19) identifies a subgroup of B-disorders CD5+ and Matutes’ score < 3, which could be of poor prognosis, based on progressive disease and unmutated status.

The role of cytogenetic and molecular testing in the diagnostics and prognostication of chronic B-cell lymphocytic leukemia

2021 ◽  
Vol 56 (3) ◽  
pp. 1-17
Author(s):  
Marta Szarawarska ◽  
Andrzej Jasiewicz ◽  
Andrzej Pluta ◽  
Joanna Niemiec
Keyword(s):  
B Cell ◽  
Predictive Factors ◽  
Chromosomal Abnormalities ◽  
Adult Population ◽  
Clinical Stage ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Molecular Testing ◽  
Mutational Status ◽  
Risk Patients

B-cell chronic lymphocytic leukemia (B-CLL) is the most frequently diagnosed leukemia in an adult population in Europe and North America. Disease pathogenesis is not well defined. The majority patients are following the “wait and watch” strategy since early treatment does not affect survival. The therapeutic decision is based on the clinical stage of disease, presence of comorbid conditions clinical disease activity as well as 11q deletion and 17p deletion status and/or mutation in the TP53 gene. Moreover, expression of CD38, ZAP70, and mutational status of IGVH gene are well-known prognostic factors. The following chromosomal abnormalities are the most frequently diagnosed in CLL: 13q14 (in 50 – 60% CLL), 11q22-23 (in 12 – 18% CLL), 17p13 (in 10% CLL) deletion, 6q (in about 6% CLL) and trisomy of chromosome 12 (in 10 – 20% CLL). However, the above-mentioned factors are not able to define all, high-risk patients. Therefore, there is an urgent need to search for new prognostic and predictive factors, which might be helpful in better classification and selection for personalized therapy for B-cell CLL patients. This prompted us to review both the well-known and new prognostic/predictive factors.

Involvement of the NOTCH1 and NOTCH2 Genes in B-Cell Lymphomagenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2072-2072
Author(s):  
Iwona Wlodarska ◽  
Kim De Keersmaecker ◽  
Jan Cools ◽  
Chris De Wolf-Peeters ◽  
Andre Bosly ◽  
...  
Keyword(s):  
B Cell ◽  
Notch Pathway ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
First Case ◽  
Structural Aberrations ◽  
Trisomy 12 ◽  
And Function ◽  
Normal Status

Abstract The NOTCH pathway is a key regulator of developmental choices, differentiation and function throughout the hematopoietic system. An aberrant activation of this pathway may underlie leukemogenesis, as shown in T-ALL cases with the rare t(7;9)(q35;q34) targeting NOTCH1 or with mutation(s) of NOTCH1 found in approximately 50% of T-ALL cases. We report here evidence for NOTCH1 and NOTCH2 rearrangements in B-cell lymphoma. Involvement of NOTCH1 was identified by the presence of dic(9;14)(q34;q32) and trisomy 12 in a case of chronic lymphocytic leukemia (CLL) at the time of transformation, and by st(9;22)(q34;q11) accompanied by t(14;18)(q32;q21)/IGH-BCL2 and t(8;14)(q24;q32)/IGH-CMYC in a follicular lymphoma (FL). FISH analysis of dic(9;14) and t(9;22) demonstrated the respective involvement of the IGH and IGL loci, and mapped both 9q34 breakpoints to the 5′ end of NOTCH1. Western blot analysis with cleaved Notch1 (Val1744) antibody was performed in both cases and hyperactive NOTCH1 signaling was found in the first case only. This particular case displayed in addition a mutation in the PEST domain of NOTCH1. No mutations, neither in the PEST, nor in HD domain of NOTCH1 (2 domains frequently mutated in T-ALL) were found in the FL case. FISH analysis of 30 additional lymphoma cases documented by structural aberrations of 9q33q34 revealed a normal status of NOTCH1. NOTCH2 rearrangement was identified by FISH in 1 out of the 3 leukemia/lymphoma cases we could collect with t(1;14)(p13;q32). This particular CLL case showed a 3-way translocation, t(1;14;18)(p13;q32;q21), targeting also BCL2. So far, this patient did not show any clinical features of CLL transformation. We hypothesize that IG-translocations affecting NOTCH genes in B-cell malignancies contribute to the lymphomagenesis by deregulating the transcription of these genes resulting in an aberrant ligand-independent NOTCH signaling. Mutation in the PEST domain of NOTCH1 as found in one case with dic(9;14) may further contribute to the process by stabilization of the aberrant product. Further molecular and immunohistochemical investigations of these cases are in progress.

Clinical Prognostic Biomarkers in Chronic Lymphocytic Leukemia and Diffuse Large B-Cell Lymphoma

2014 ◽  
Vol 139 (5) ◽  
pp. 602-607 ◽  
Author(s):  
Elizabeth C. Chastain ◽  
Eric J. Duncavage
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Large B Cell Lymphoma ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Large B Cell

Context Diffuse large B-cell lymphoma and chronic lymphocytic leukemia are 2 of the most common B-cell lymphomas in adults. Both diffuse large B-cell lymphoma and chronic lymphocytic leukemia share heterogeneous outcomes, and the use of prognostic biomarkers to better stratify risk in these patients has now become commonplace. Objective To review chronic lymphocytic leukemia and diffuse large B-cell lymphoma biomarkers commonly used in the clinical laboratory, which can be divided into the following 3 main groups by testing methodology: chromosomal based (including fluorescence in situ hybridization and cytogenetics), expression based (including immunohistochemistry and flow cytometry), and DNA based (including gene sequencing for somatic mutations and IGVH mutational status). Data Sources Review of recent literature. Conclusions In chronic lymphocytic leukemia, important biomarkers include expression of CD38 and ZAP-70, IGVH mutational status, somatic mutations in TP53 and NOTCH1, and abnormalities in chromosomes 11, 12, 13q, and 17. In diffuse large B-cell lymphoma, important biomarkers include chromosomal rearrangement of BCL2, BCL6, and MYC and expression of CD5, BCL2, and CD43, as well as somatic mutations in TP53 and BCL6.

ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL)

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3584-3592 ◽  
Author(s):  
Sarah J. Richardson ◽  
Christine Matthews ◽  
Mark A. Catherwood ◽  
H. Denis Alexander ◽  
B. Sean Carey ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Actin Polymerization ◽  
Chromosomal Abnormalities ◽  
Lymphocytic Leukemia ◽  
Cellular Migration ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

Molecular markers like IgVH mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70+ CLL B cells respond in vitro more readily than ZAP-70– CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70+ CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-α, a survival factor produced by stromal cells) compared with ZAP-70– cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70+ but not ZAP-70– CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70+ disease.

CD26 Expression in Mature B-Cell Neoplasia: Its Possible Role as a New Prognostic Marker in B-CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4670-4670
Author(s):  
Lilla Cro ◽  
Nadia Zucal ◽  
Sonia Fabris ◽  
Antonino Neri ◽  
Marta Lionetti ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Abnormalities ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Favourable Outcome ◽  
Lymphocytic Leukemia ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Mutational Status ◽  
Cd26 Expression

Abstract CD26 (dipeptidyl peptidase IV, DPP IV) is a multifunctional type II cell surface glycoprotein that is widely expressed on T and natural killer cells, as well as on epithelial, endothelial and acinar cells of different tissues; its expression on B cells is very low but it is greatly upregulated following activation. We evaluated, by means of flow cytometry, the expression of CD26 in various types of B-cell lymphoid tumors: Follicular Lymphoma (Fo-Ly, 12 cases), Mantle cell Lymphoma (MCL, 12 cases) Multiple Myeloma (MM, 20 cases), Hairy cell Leukemia (HCL, 12 cases), B-cell Chronic Lymphocytic Leukemia (B-CLL, 112 cases), CD5 negative B-cell Chronic Lymphoproliferative Diseases (CD5neg-B-CLPD, 20 cases) and Diffuse Large cell Lymphoma (DLCL, 12 cases). CD26 expression was absent or low of Fo-Ly and MCL, high on MM and HCL, variable on B-CLL, CD5neg-B-CLPD and DLCL. Fluorescence intensity of positive cells was dim in B-CLL and CD5neg-B-CLPD, heterogeneous in DLCL, and bright in HCL and MM. Interestingly, in CLL patients, CD26 expression was significantly correlated with CD49d and CD38 expressions (p<0.0001); moreover Spearman’s test revealed a significant correlation between CD26, CD38 or ZAP-70 expression and IgVH mutational status (p<0.0001). We also found a significant correlation between CD26 expression and the presence of FISH chromosomal abnormalities grouped on the basis of their prognostic relevance (p<0.0001). After a median follow-up of 36 months, 65/107 CLL pts were treated; taking 10% of positive cells as best cut-off, Kaplan-Meier curves showed that the time without therapy was significantly longer for CD26 negative cases compared with CD26 positive cases (P <0.0001). Moreover the concordant negativity of CD26 and CD38, or ZAP-70 and the combination of CD26 negativity with IgVH mutated status, identified subsets of CLL patients with a favourable outcome in terms of need of therapy.

Heterogeneous chromosomal aberrations generate 3' truncations of the NFKB2/lyt-10 gene in lymphoid malignancies

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3850-3860 ◽  
Author(s):  
A Migliazza ◽  
L Lombardi ◽  
M Rocchi ◽  
D Trecca ◽  
CC Chang ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Translocation ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Sequencing Analysis ◽  
Lymphoid Malignancies ◽  
Lymphoid Neoplasia ◽  
Carboxy Terminal

The NFKB2(lyt-10) gene codes for a protein that is a member of the NK- kappa B/rel family of transcription factors containing a DNA-binding rel domain and a carboxy-terminal ankyrin-like domain. The NFKB2 gene represents a candidate proto-oncogene, since it has been found to be involved in a chromosomal translocation t(10;14)(q24;q32) in one case of B-cell lymphoma and in gene rearrangements in various types of lymphoid malignancies. To elucidate the structural and functional consequences of NFKB2 rearrangements, we report the molecular characterization of three novel rearranged NFKB2 genes in lymphoid tumors. In one case of multiple myeloma (MM), cloning and sequencing analysis of reciprocal breakpoint sites showed that they occurred within intron 15 of the NFKB2 gene and led to the complete deletion of the 32 portion of the gene coding for the ankyrin domain. Fluorescent in situ hybridization (FISH) analysis showed that the novel regions involved in the NFKB2 rearrangement originated from chromosome 7q34, thus implying the occurrence of a t(7;10)(q34;q24) reciprocal chromosomal translocation. In one case of T-cell cutaneous lymphoma (CTCL) and in one of B-cell chronic lymphocytic leukemia (B-CLL), NFKB2 rearrangements occurred, respectively, within exons 18 and 20 of the gene and involved recombinations with distinct regions of chromosome 10q24. Molecular analysis suggested that these rearrangements may occur as a consequence of small internal chromosomal deletions. In both of these cases, the rearrangements led to specific carboxy-terminal truncations of NFKB2 generating abnormal transcripts that coded for proteins lacking portions of the ankyrin domain. These proteins localize in the nucleus, suggesting their constitutive activation in vivo. Overall, our results indicate that NFKB2 rearrangements in lymphoid neoplasia may occur by heterogeneous mechanisms, including internal chromosomal deletion or chromosomal translocation. The common consequence of these rearrangements appears to be the deletion of 32 sequences of NFKB2 leading to the production of carboxy-truncated constitutively nuclear proteins that may be involved in tumorigenesis.

The utility of molecular profiling in clinical trial enrollment and monitoring.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 12-12
Author(s):  
Matthew Thomas Hardison ◽  
James Stover
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
B Cell Lymphoma ◽  
Molecular Profiling ◽  
Lymphocytic Leukemia ◽  
Controlled Clinical Trial ◽  
Fish Analysis ◽  
Clinical Trial Enrollment

12 Background: With the growing number of therapies that are directed against specific biomarkers, or discrete subsets of cancers, it is increasingly important to prospectively identify the most appropriate subjects for enrollment in a randomized, controlled clinical trial. Historically, clinical trial enrollment was strictly guided phenotypically. Subjects were included in a study simply based on presentation and disease progression, regardless of any underlying molecular mechanisms. Methods: Aegis involves the use of multiple molecular genetic procedures to investigate clinical trial subjects, whether for enrollment or disease monitoring. Fluorescent in situ hybridization (FISH) to detect chromosomal aberrations and single-gene Sanger sequencing are utilized to identify subjects with abnormalities associated with cancers such as chronic lymphocytic leukemia (CLL) prior to enrollment. Gene expression analysis using Nanostring digital RNA counting to stratify diffuse large B-cell lymphoma subjects, B-cell receptor clonal assessment through IgVH analyses, and next generation sequencing are also used to provide vital data throughout the clinical trial process. Results: The use of modern molecular genetic techniques increases and improves the data available to companies for subject enrollment, stratification, and monitoring throughout a clinical trial. Genetic analysis can indicate disease response through reduced mutation burden, changes in clonality of tumor cells, or a resolution of the underlying genetic cause. This data, in conjunction with clinical presentation is employed by pharmaceutical companies to design subsequent trial stages or identify additional potential disease states as targets for a particular therapeutic. Specifically, TP53 sequencing and FISH analysis in CLL are vital to assigning risk stratification to potential subjects. Conclusions: With the advent of immunotherapy and the precision nature of such therapeutic development, molecular profiling will continue to be a vital tool in the identification of optimal clinical trial subjects. This could ultimately lead to smaller, more definitive clinical trials, which would be helpful to clinicians and patients in terms of cost and time.

Integrative structural variant and breakpoint detection using optical genome mapping in a patient with a transformed diffuse large B-cell lymphoma from chronic lymphocytic leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19511-e19511
Author(s):  
Jiachi Wang ◽  
Andy Pang ◽  
Karl Hong ◽  
Jill Lai ◽  
Dipa Roychoudhury ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Genome Mapping ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Significant Finding ◽  
Large B Cell Lymphoma ◽  
Large B Cell

e19511 Background: The finding of complex karyotypes has been a clinically significant finding in cancers of advanced stage or during cancer progression. Conventional cytogenetic and FISH analyses have been limited by the low-resolution of chromosomes and the number of FISH probes which can be implemented in one assay. Recent study revealed the potential of using optical genome mapping to decipher the architecture of cancer genome at nucleotide level. Methods: Karyotyping, FISH and optical genome mapping of bone marrow specimen. Results: We reported on a 63-year-old female with chronic lymphocytic leukemia for nine years and transformed to diffuse large B-cell lymphoma (DLBCL). The karyotype revealed a hypodiploid chromosomal complement: 42,X,-X,der(2)t(2;?;8)(p25;?;q11.2),t(2;9)(q3?5;p2?2),der(4)t(4;?;8)(p16;?;q11.2)t(4;15)(q35;q15),-8,-15,dic(17;21)(p11.2;p11.2),der(18)t(8;18)(q21.2;p11.32)[12]/46,XX[8]. FISH analysis showed loss of TP53, monosomy 8 with 3-5 copies of the Myc genes. Optical genome mapping analysis revealed 12 insertions, 29 deletions, 8 duplications, 6 intrachromosomal translocations and 12 interchromosomal translocations. Whole genome analysis identified multiple gains of 2p, 8p and 8q, losses of 9p, 15q and 17p. The breakpoints of two unbalanced translocation and one complex chromosomal rearrangement have been narrowed down to nucleotide resolution: ogm[GRCh37] t(2;9)(q34;p21.2) g.[chr2:211,281,003::chr9:26,532,620], ogm t(2;8)(p25.3;p23.3) g.[chr2:15,924::chr8:215,177] and ogm der(4)t(8q24.3→8q21.13→2p24.2→2q34→4p15.2→4q34.3→15q15.1) g.[chr8:80,461,191::chr2:18,079,530→chr2:211,274,379::chr4:26,381,729→chr4:180,989,408::chr15:42,404,514]. Conclusions: Integrative analysis using conventional cytogenetic and molecular cytogenomic methodologies unveil the complex architectural alterations of caner genome. The resolution achieved by optical genome mapping would potentially lead to discovery of carcinogenic mechanisms, new fusion genes, prognostic and therapeutic markers.

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.

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