scholarly journals The Traf2DNxBCL2-tg Mouse Model of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Recapitulates the Biased IGHV Gene Usage, Stereotypy, and Antigen-Specific HCDR3 Selection of Its Human Counterpart

2021 ◽  
Vol 12 ◽  
Author(s):  
Gema Perez-Chacon ◽  
Juan M. Zapata
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Differentiation ◽  
Small Lymphocytic Lymphoma ◽  
Immunodeficient Mice ◽  
Ighv Gene ◽  
Human Counterpart ◽  
Gene Usage

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) is a heterogeneous disease consisting of at least two separate subtypes, based on the mutation status of the immunoglobulin heavy chain variable gene (IGHV) sequence. Exposure to antigens seems to play a role in malignant transformation and in the selection and expansion of more aggressive CLL clones. Furthermore, a biased usage of particular IGHV gene subgroups and the existence of stereotyped B-cell receptors (BCRs) are distinctive characteristics of human CLL. We have previously described that Traf2DN/BCL2 double-transgenic (tg, +/+) mice develop CLL/SLL with high incidence with aging. In this model, TNF-Receptor Associated Factor (TRAF)-2 deficiency cooperates with B cell lymphoma (BCL)-2 in promoting CLL/SLL in mice by specifically enforcing marginal zone (MZ) B cell differentiation and rendering B cells independent of BAFF for survival. In this report, we have performed the sequencing of the IGHV-D-J rearrangements of B cell clones from the Traf2DN/BCL2-tg+/+ mice with CLL/SLL. The results indicate that these mice develop oligoclonal and monoclonal B cell expansions. Allotransplantation of the oligoclonal populations into immunodeficient mice resulted in the preferential expansion of one of the parental clones. The analysis of the IGHV sequences indicated that 15% were mutated (M) and 85% unmutated (UM). Furthermore, while the Traf2DN/BCL2-tg-/- (wild-type), -/+ (BCL2 single-tg) and +/- (Traf2DNDN single-tg) littermates showed the expression of various IGHV gene subgroups, the CLL/SLL expanded clones from the Traf2DN/BCL2-tg+/+ (double-transgenic) mice showed a more restricted IGHV gene subgroup usage and an overrepresentation of particular IGHV genes. In addition, the HCDR3-encoded protein sequence indicates the existence of stereotyped immunoglobulin (Ig) in the BCRs and strong similarities with BCR recognizing autoantigens and pathogen-associated antigens. Altogether, these results highlight the remarkable similarities between the CLL/SLL developed by the Traf2DN/BCL2-tg+/+ mice and its human counterpart.

Usage of IGHV4-39 with Stereotypic B Cell Receptor Is An Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 778-778
Author(s):  
Davide Rossi ◽  
Valeria Spina ◽  
Michaela Cerri ◽  
Clara Deambrogi ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Control Analysis ◽  
Ighv Gene ◽  
Gene Usage

Abstract Richter’s syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, mainly occurring as diffuse large B-cell lymphoma (DLBCL). The biology of CLL transformation to RS is poorly understood and knowledge on risk factors of RS development is scant. We tested whether IGHV gene usage and stereotypic B cell receptor (BCR) at CLL diagnosis have an impact on RS transformation. The first step of the study consisted of a case-control analysis comparing IGHV gene usage and prevalence of stereotypic HCDR3 in RS (n=69; all DLBCL) versus a control group (n=715) of CLL that had not transformed to RS. The second step consisted of an actuarial assessment of the impact of IGHV gene usage and stereotypic HCDR3 at CLL diagnosis, on the risk of subsequent transformation to RS in a cohort of 754 CLL, of which 39 had transformed to RS. Comparison of IGHV usage in unmutated RS versus unmutated control CLL documented that IGHV4-39 was the sole gene preferentially utilized (6/48, 12.5% vs 5/277, 1.8%, respectively, p=.002) by RS. Prevalence of stereotypic HCDR3 was significantly higher in RS compared to non-transformed CLL when considering all cases (RS: 50.7% vs non-transformed CLL: 22.2%; p<.000001), unmutated cases only (RS: 58.3% vs non-transformed CLL: 35.7%; p=.003), and mutated cases only (RS: 33.3% vs non-transformed CLL: 13.7%; p=.022). Compared to non-transformed CLL, RS preferentially utilized BCR belonging to a subset characterized by rearrangement of unmutated IGHV4-39/IGHD6-13/IGHJ5 genes (2/159, 1.2% vs 5/35, 14.3%, respectively; p=.002). All cases with stereotypic IGHV4-39 carried +12 as the sole FISH abnormality. After a median follow-up of 41.1 months, 39/754 CLL had transformed to RS. Univariate analysis documented: shorter time to transformation in CLL utilizing IGHV4-39 (5-year risk: 35.4%) compared to CLL utilizing other IGHV genes (5-year risk: 5.6%) (p<.000001); higher risk of RS in CLL utilizing stereotypic HCDR3 (5-year risk: 14.2%) compared to CLL without stereotypic HCDR3 (5-year risk: 3.9%) (p<.00001). CLL with stereotypic HCDR3 and IGHV homology 98% showed a significantly higher risk of transformation (5-year risk: 18.4%) compared to CLL with IGHV homology 98% but without stereotypic HCDR3 (5-year risk: 6.8%) (p=.006). Also, stereotypic HCDR3 identified a CLL subgroup that, despite presenting with IGHV homology <98%, showed an increased risk of RS (p=.040). This observation indicates that stereotypic HCDR3 is not a surrogate of IGHV homology for RS prediction. We then tested the independent predictive value for RS transformation of IGHV4-39 usage and of stereotypic HCDR3. Multivariate analysis selected IGHV4-39 usage (HR: 4.25; p=.002) and stereotypic HCDR3 at CLL diagnosis (HR: 3.08; p=.002) as independent predictors of RS transformation. The observation that all RS utilizing IGHV4-39 carried stereotypic HCDR3 prompted investigation of the interaction between IGHV4-39 usage and stereotypic HCDR3 in the model. Multivariate analysis selected the interaction between IGHV4-39 usage and stereotypic HCDR3 at CLL diagnosis as the strongest independent predictor of RS transformation (HR: 5.13; p=.001). The relevance of the interaction between IGHV4-39 and stereotypic HCDR3 was confirmed by bivariate log rank analysis. Accordingly, CLL utilizing both IGHV4-39 and stereotypic HCDR3 were identified as the disease category with highest risk of transformation (5-year risk: 68.7%). Transformation to RS and progression to symptomatic disease according to NCI Working Group guidelines are distinct events in CLL. Accordingly, neither IGHV4-39 usage nor stereotypic HCDR3 affected the risk of CLL progression occurring without transformation to RS. IGHV4-39 usage and stereotypic HCDR3 may be appropriate biological markers for RS prediction since: these markers predict RS in a fashion that is independent of other clinical and biological features; given the widespread use of IGHV sequencing for CLL prognostication, information on IGHV4-39 and stereotypic HCDR3 may be obtained at CLL diagnosis without additional testing; and importantly all CLL with concomitant IGHV4-39 usage and stereotypic HCDR3 ultimately transform to RS. A close monitoring and a careful biopsy policy may be of help for early recognition of RS transformation in patients carrying IGHV4-39 usage and stereotypic HCDR3.

scholarly journals Histiocytic Sarcoma: Review, Discussion of Transformation From B-Cell Lymphoma, and Differential Diagnosis

2018 ◽  
Vol 142 (11) ◽  
pp. 1322-1329 ◽  
Author(s):  
Stephanie L. Skala ◽  
David R. Lucas ◽  
Rajan Dewar
Keyword(s):  
Differential Diagnosis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Histiocytic Sarcoma ◽  
Lymphocytic Leukemia ◽  
Western Hemisphere ◽  
Low Grade ◽  
Small Lymphocytic Lymphoma

Context.— Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course that can arise de novo or from a low-grade B-cell lymphoma. In particular, chronic lymphocytic leukemia/small lymphocytic lymphoma is a very common malignancy in the Western hemisphere, and most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma have an indolent course and behavior. However, 2% to 8% of chronic lymphocytic leukemia/small lymphocytic lymphoma cases transform. Histiocytic sarcomatous transformation is rare and portends poor prognosis. Objective.— To review the clinical features, morphology, and key points related to the differential diagnosis for histiocytic sarcoma. We discuss recent understanding of the biology underlying transformation. Data Sources.— University of Michigan case and review of pertinent literature about histiocytic sarcoma and morphologic differential diagnosis. Conclusions.— Histiocytic sarcoma is a rare histiocytic neoplasm that can arise as a result of transdifferentiation from low-grade B-cell lymphomas, and has a wide differential diagnosis including other histiocytic/dendritic cell neoplasms, myeloid neoplasms, lymphomas, melanoma, and carcinoma. However, some key morphologic and immunohistochemical features allow for accurate classification.

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 The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia

2016 ◽  
Vol 7 (6) ◽  
pp. 321-329 ◽  
Author(s):  
Valentín Ortíz-Maldonado ◽  
Pablo Mozas ◽  
Julio Delgado
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Therapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Hallmarks Of Cancer ◽  
Lymphoid Malignancies

B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.

An unusual case of indolent B-cell lymphoma with distinct chronic lymphocytic leukemia and marginal zone differentiation according to the site of involvement

2005 ◽  
Vol 46 (9) ◽  
pp. 1369-1374 ◽  
Author(s):  
Lucile Baseggio ◽  
Sophie Gazzo ◽  
Evelyne Callet-Bauchu ◽  
Alexandra Traverse-Glehen ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Unusual Case ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia

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

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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