Translocations Involving 8q24 in Burkitt Lymphoma and Other Malignant Lymphomas: A Historical Review of Cytogenetics in the Light of Todays Knowledge

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2814-2814
Author(s):  
Evert-Jan Boerma ◽  
Reiner Siebert ◽  
Michael Baudis ◽  
Philip Kluin
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Age Distribution ◽  
Classification Systems ◽  
Proliferation Index ◽  
Molecular Profile ◽  
Steady Increase ◽  
B Cell Lymphomas ◽  
The Core ◽  
Core Subset

Abstract Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, i.e. the translocation t(8;14) (q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B cell lymphomas such as a small subset of diffuse large B cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this study the “Mitelman Database of Chromosome Aberrations in Cancer”, harboring the majority of all published neoplasia related karyotypes, was explored to define a cytogenetic profile of “true” BL. To that end a core subset of BL was defined by a histologic diagnosis of BL, the presence of a t(8;14), t(2;8) or t(8;22) indicating a MYC/IG breakpoint, and the absence of a 3q27/BCL6, 18q21/BCL2 or 11q13/CCND1 breakpoint additional to the 8q24/MYC breakpoint. These core BL (N=481) showed a very low complexity of chromosomal changes, with 40% of the cases having the IG-MYC fusion as the sole abnormality; in the remaining cases additional recurrent and partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. No differences were found between pediatric (N=205) and adult patients (N=215). Moreover, no differences were found between such core BL cases published before (N= 280) and after 1994 (N=201) indicating that historical changes in classification systems had no major impact on this profile. The genetic profiles and age distribution of the core subset were significantly different from BL with an 8q24 breakpoint not affecting one of the three IG loci (N=13), lymphomas that were diagnosed as BL but had a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1 additional to a breakpoint at 8q24/MYC (“double hit BL”; N=44), and from other morphological types of lymphomas with an 8q24/MYC breakpoint (N=327; 256/327 cases had an IG-MYC breakpoint). These groups showed an other age distribution and a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint (N=108) might have been heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index, and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. Additionally, a high number of non-specific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL. Finally, the steady increase in age of lymphomas that mimic BL strongly emphasizes that there is no distinct age at which a pathologist can safely make a diagnosis of BL without any ancillary cytogenetic or molecular studies.

scholarly journals Simple karyotype and bcl-6 expression predict a diagnosis of Burkitt lymphoma and better survival in IG-MYC rearranged high-grade B-cell lymphomas

2010 ◽  
Vol 23 (7) ◽  
pp. 909-920 ◽  
Author(s):  
Adam C Seegmiller ◽  
Rolando Garcia ◽  
Rong Huang ◽  
Atousa Maleki ◽  
Nitin J Karandikar ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
High Grade ◽  
B Cell Lymphomas

Anomalous High p27/KIP1 Expression in a Subset of Aggressive B-Cell Lymphomas Is Associated With Cyclin D3 Overexpression. p27/KIP1—Cyclin D3 Colocalization in Tumor Cells

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 765-772 ◽  
Author(s):  
Margarita Sánchez-Beato ◽  
Francisca I. Camacho ◽  
Juan C. Martı́nez-Montero ◽  
Ana I. Sáez ◽  
Raquel Villuendas ◽  
...  
Keyword(s):  
B Cell ◽  
Cyclin D1 ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Cyclin D3 ◽  
Nuclear Accumulation ◽  
Proliferation Index ◽  
B Cell Lymphomas ◽  
Proliferating Cells ◽  
P27 Kip1

Abstract p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt’s lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt’s cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.

Anomalous High p27/KIP1 Expression in a Subset of Aggressive B-Cell Lymphomas Is Associated With Cyclin D3 Overexpression. p27/KIP1—Cyclin D3 Colocalization in Tumor Cells

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 765-772 ◽  
Author(s):  
Margarita Sánchez-Beato ◽  
Francisca I. Camacho ◽  
Juan C. Martı́nez-Montero ◽  
Ana I. Sáez ◽  
Raquel Villuendas ◽  
...  
Keyword(s):  
B Cell ◽  
Cyclin D1 ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Cyclin D3 ◽  
Nuclear Accumulation ◽  
Proliferation Index ◽  
B Cell Lymphomas ◽  
Proliferating Cells ◽  
P27 Kip1

p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt’s lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt’s cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.

scholarly journals Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma

Haematologica ◽  
2013 ◽  
Vol 99 (4) ◽  
pp. 726-735 ◽  
Author(s):  
S. M. Aukema ◽  
M. Kreuz ◽  
C. W. Kohler ◽  
M. Rosolowski ◽  
D. Hasenclever ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Biological Characterization ◽  
B Cell Lymphomas

scholarly journals Gene Expression Analysis Uncovers Similarity and Differences Among Burkitt Lymphoma Subtypes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2494-2494
Author(s):  
Pier Paolo Piccaluga ◽  
Giulia De Falco ◽  
Manjunat Kustagi ◽  
Anna Gazzola ◽  
Annalisa Astolfi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
B Cell ◽  
Burkitt Lymphoma ◽  
Who Classification ◽  
Cell Cycle Control ◽  
B Cell Lymphomas ◽  
Over Expression

Abstract Abstract 2494 Background. Burkitt lymphoma (BL) is currently listed in the WHO classification of lymphoid tumors as a single genetic and morphological entity with variation in clinical presentation. In particular, three clinical subsets of BL are recognized: endemic (eBL), sporadic (sBL) and immunodeficiency associated (ID-BL). Each affects different populations and can present with different features. So far, possible differences in their gene expression profiles (GEP) have not been investigated. In this study we aimed to 1) assess whether BL subtypes present with differences in their GEP; 2) investigate the relationship of the different BL subtypes with the non-neoplastic cellular counterparts; 3) Identify genes and programs specifically deregulated in BLs and possibly contributing to the malignant phenotype. Methods. We studied by GEP 128 cases of B-cell derived malignancies and 20 samples of normal B-cell subpopulations GEP analysis. In particular, we included 40 BLs (13 eBLs, 21 sBLs 6 HIV-BLs), 40 follicular lymphomas, 10 chronic lymphocytic leukemias, 10 GCB-type diffuse large B-cell lymphomas, 10 ABC-type DLBCL, 5 primary mediastinal B-cell lymphomas, 13 HIV-related DLBCL, as well as 10 germinal center (GC), 5 naïve and 5 memory cells samples. GEP results were confirmed by dividing BL cases into training and test subgroups. In addition, as further validation, we performed immunohistochemistry (IHC) on tissue microarrays containing 85 BL cases as well as functional assays in vitro and in vivo, by focusing on the role of RBL2, a tumor suppressor gene involved in cell cycle control and mutated in eBL. Specifically, we used cell transfection and shRNAs (for mimicking MYC over-expression and RBL2 silencing), soft agar and invasion capability assays, and xenografted mouse models. Results. First, we found that BLs constitute a unique molecular entity, with a relatively homogeneous GEP, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. However, by supervised analysis, we found that BL subtypes presented slight differences in their GEPs. Particularly, eBLs and ID-BLs appeared to be almost identical, diverging from sBLs. Specifically, they varied for genes involved in cell cycle control, BCR-signaling, and TNF/NFKB-pathways. Of note, eBLs and ID-BLs on one hand, and sBLs on the other (roughly corresponding to EBV+ vs. EBV− cases) also differed for genes target of mi-R127a, which is altered in EBV+ cases as a direct consequence of viral integration. To further investigate cell cycle regulation in BLs, we inferred a network of RBL2-depending genes by reverse engineering, by uncovering possible RBL2 transcriptional targets. Interestingly, we found that eBL and sBL diverged for genes belonging to such network. Notably, we provided evidences that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In particular, lymphoblastoid cells engineered to carry both MYC over-expression and RBL2 silencing presented with increased colony formation and matrix invasion capabilities, and higher efficiency in inducing tumor formation in nude mice if compared to single transfectants (MYC+ or RBL2−). Moreover, as the present WHO classification does not definitely identify the counterpart of eBL, we compared BLs GEP to those of normal B-cells. We found that all BL subtypes were intimately related to GC cells (by showing an early stage GC differentiation arrest), differing from them for molecules specially involved in cell proliferation, immune response, and signal transduction. Finally, as further validation of GEP, we studied by IHC the expression of SPARC and CYR61, two molecules involved in human tumorigenesis. Indeed, they turned out to be consistently expressed by neoplastic elements in all instances, as indicated by GEP analysis. Conclusions. Our study provided substantial insights on the pathobiology of BLs, by offering novel evidences which may be relevant for its classification and possibly future treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Pathologic Spectrum of Bone Marrow Involvement by Double- and Triple-hit Lymphomas

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S96-S97
Author(s):  
H Iqbal ◽  
A Harrington ◽  
S H Kroft
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Bone Marrow Involvement ◽  
Laboratory Data ◽  
Large Cell ◽  
Proliferation Index ◽  
High Grade ◽  
B Cell Lymphomas ◽  
Lymphoma Cells ◽  
Pathologic Features

Abstract Introduction/Objective B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (double- and triple-hit lymphomas, DHL/THL) are a distinct entity due to shared biology and aggressive behavior, exhibiting poor outcomes with standard therapies. While pathologic features of DHL/THLs in primary sites have been well described, little information is available regarding the clinicopathologic features of bone marrow involvement by this entity. Methods/Case Report Files were searched from 2010-2020 for all DHL/THLs. Since mid-2016, all aggressive B-cell lymphomas were reflexed to DHL/THL FISH testing. Prior to that, criteria for performing FISH varied. Clinical and laboratory data were obtained through chart review. Both BM and primary diagnostic specimens were reviewed when possible. Results (if a Case Study enter NA) There were 46 DHL/THL cases with initial staging BM evaluations, of which 13 (28%) were positive for DHL/THL; 11 were available for review (5F:6M; 28-95 years). All patients with positive BMs were stage 3 or 4 irrespective of the BM findings. Lymphoma cytology in positive BMs was blastoid in 6, large cell in 2, and high grade, NOS in 3. The cytology in primary tissues was not significantly associated with the rate of marrow involvement. PB smears were available for 9/11 BM(+) cases; of these, 6 (66.7%) had circulating lymphoma cells in the blood, ranging from rare to greater than 40% lymphoma cells (median, 4%). Lymphoma cells with cytoplasmic vacuoles were present in 5 cases (45%). No BM infiltrates had a starry-sky appearance. Infiltration patterns included diffuse (3), diffuse and interstitial (3), and interstitial (3). One exhibited only rare, scattered lymphoma cells in the aspirate and core biopsy, and another with large cell morphology showed random focal (nodular) and focally paratrabecular infiltration. The proliferation index in the marrow infiltrates ranged from 50% to >90% (median, 65%). Flow cytometry was positive in 9 of 10 cases; the single negative study was from an outside institution Conclusion Our study demonstrates 28% of DHL/THLs show BM involvement at diagnosis. Notably, the peripheral blood was involved in 2/3 of cases with marrow infiltration (13% of total cases), ranging from rare circulating cells to frank leukemic involvement. Cytologically, the marrow infiltrates were predominantly blastoid or high grade NOS. Marrow infiltrates generally displayed leukemic rather than lymphomatous patterns of involvement.

scholarly journals Burkitt-Like Lymphoma with 11q Aberration: A Case Report and Review of a Rare Entity

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Sepideh N. Asadbeigi ◽  
Chelsey D. Deel
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Neck Mass ◽  
Lymphoid Cells ◽  
High Grade ◽  
Rare Entity ◽  
B Cell Lymphomas ◽  
Cytogenetic Studies ◽  
Children And Young Adults ◽  
Gain Loss

Burkitt-like lymphoma with 11q aberration is a rare diagnostic entity commonly occurring in children and young adults with a nodal presentation. This entity shares many similar morphologic and immunophenotypic features with conventional Burkitt lymphoma and other aggressive B-cell lymphomas, making its recognition challenging. However, the presence of its characteristic 11q gain/loss pattern is helpful in the diagnosis. We report a case of Burkitt-like lymphoma presenting as a right neck mass in a 17-year-old female patient that demonstrated no improvement with antibiotic therapy. The neoplasm displayed a diffuse proliferation of intermediate-sized atypical lymphoid cells with prominent nucleoli in a background of apoptotic debris, morphologically raising concern for conventional Burkitt lymphoma. Subsequent immunohistochemical and cytogenetic studies established the most likely diagnosis of Burkitt-like lymphoma with 11q aberration. Though rare, Burkitt-like lymphoma exhibits significant morphologic overlap with other high-grade B-cell lymphomas, making it an important entity to consider on the differential diagnosis of these lesions.

Recurrent Mutations in Focal Adhesion Genes Including the RhoA Signaling Axis Are a Defining Feature of Germinal Center (GC) Derived B Cell Lymphomas and Promote Aberrant Migration and Cellular Adhesion within the GC Niche

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 558-558
Author(s):  
Jane Healy ◽  
Rachel E Rempel ◽  
Andrea B. Moffitt ◽  
Nicholas Davis ◽  
Jenny Zhang ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Focal Adhesion ◽  
Germinal Center ◽  
Burkitt Lymphoma ◽  
Cellular Adhesion ◽  
Filamentous Actin ◽  
B Cell Lymphomas ◽  
Total N ◽  
Rhoa Signaling

Abstract Nonhodgkin lymphomas (NHLs) are among the most common cancer subtypes, with approximately >350,000 new cases diagnosed annually worldwide. The majority of NHLs arise from germinal center (GC)-derived B cells. Through network analysis we demonstrated that mutations in focal adhesion pathway genes, including RHOA and GNA13, are a defining characteristic of GC-derived B cell lymphoma, occurring in ~75% of the samples analyzed, and less than 10% of ABC DLBCLs and mantle cell lymphomas. We and others have previously described RHOA mutations in GC-derived B cell lymphomas including DLBCL and Burkitt lymphoma, but the functional consequences of these mutations remain unknown. We examined the patterns of RHOA mutation in DLBCL through targeted gene sequencing in 335 tumor-normal pairs. Cell of origin analysis revealed that there were 128 GCB DLBCLs in this group, with RHOA mutations occurring in 15 (11.7%) of GCB cases and none of the 207 ABC cases. RHOA mutations also occurred in 10% of Burkitt lymphoma cases (total N=66) and zero mantle cell lymphoma cases (total N=54). All the RHOA mutations were missense, and were predicted computationally to be of high impact. A significant proportion of the identified RHOA mutations affect evolutionarily conserved residues within the protein's GTP binding domain, further suggesting a functional importance. Interestingly, inactivating G17V mutations, found in 15% of peripheral T cell and 35-70% of angioimmunoblastic T cell lymphomas, never occurred in DLBCLs. RHOA is thought to signal downstream of GNA13 in a variety of cell types to regulate cellular adhesion and migration. In our study, human mutations in GNA13 and RHOA were mutually exclusive, and GC B cell specific GNA13 deletion in the AID-Cre Gna13 mouse model resulted in reduced levels of active RHOA, suggesting a pathway effect. To determine if the altered migration patterns noted in GNA13 deficient mice were due to loss of RHOA signaling, we crossed RhoA conditional knockout mice with mice expressing Cre under the AID promoter to generate deletion of RhoA exclusively in GC B cells. We then compared these mice with AID-Cre Gna13 knockout mice in parallel experiments. We found that GNA13 deficient mice demonstrate altered GC B migration dynamics, evidence of GC zonal disorganization, and reduced levels of filamentous actin. We also found that GNA13 is required for focal adhesion formation in the human Burkitt lymphoma derived cell line Raji. Similar to the GNA13 deficient state, we found that RHOA deficient GC B cells have altered dark zone and light zone dynamics, with an increased proportion of GC B cells expressing GC light zone markers, and reduced levels of filamentous actin. These data suggest that focal adhesion genes, including RHOA and GNA13, may promote lymphoma in GC B cells via aberrant migration and cellular adhesion, processes normally essential to intrazonal cycling, affinity selection, and GC B cell maturation. To our knowledge, this represents the in vivo characterization of RHOA in GC B cells and RHO mutations in B cell lymphomas and points to an important oncogenic role for RHOA in the germinal center niche. Disclosures No relevant conflicts of interest to declare.

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