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.

NOTCH1 Is Targeted by Ig Translocations in NHL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4339-4339
Author(s):  
Iwona Wlodarska ◽  
Chris De Wolf-Peeters ◽  
Jan Cools ◽  
Francesca Minnei ◽  
Andre Bosly ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Supt1 Cell ◽  
Rapid Progression ◽  
Fish Analysis ◽  
Notch1 Signaling ◽  
First Case ◽  
Structural Aberrations ◽  
Trisomy 12

Abstract NOTCH1 signaling is required for normal T cell development. Its aberrant activation by either the rare t(7;9) translocation or frequent mutation(s) in T-ALL points to an important role of this gene in T cell lymphomagenesis. So far, a pathogenetic role for NOTCH1 in B-cell malignancies is unknown. We report here evidence for NOTCH1 rearrangements in B-cell lymphoma. Two novel 9q34 translocations involving either the 14q32/IGH or the 22q11/IGL locus were identified in 2 patients with respectively, Richter syndrome (RS) and follicular lymphoma (FL). The first case showed a clone with a sole trisomy 12 detected by FISH in 25% of interphase cells and a subclone with an additional dic(9;14)(q34;q32) in 60% of cells from a lymph node sample. The karyotype of the FL case was characterized by the typical t(14;18)(q32;q21)/IGH-BCL2 accompanied by additional t(8;14)(q24;q32)/IGH-CMYC and t(9;22)(q34;q11). FISH analysis of dic(9;14) and t(9;22) using a set of BAC clones mapped both 9q34 breakpoints to the 5′end of NOTCH1. These breakpoints were different from the breakpoint of t(7;9)(q35;q34) (intron 24), as demonstrated by FISH analysis of the T-ALL SUPT1 cell line. NOTCH1 rearrangements showed to be rare in B-NHL. Any of the additional 30 lymphoma cases with structural aberrations of 9q34 analyzed by FISH showed rearrangement of this gene. So far, aberrant activation of NOTCH1 in the reported cases with dic(9;14) and t(9;22) could not be documented: both lymphomas but also 9 control CLL and FL cases without 9q34 aberrations revealed expression of NOTCH1 mRNA by RT-PCR, its ligand JAGGED2 and its transcriptional target HES1. This expression pattern indicates a ligand-driven NOTCH1 signaling in all analyzed cases, possibly reflecting its physiological activation in progenitor B cells and thus, masking the presumed aberrant activation of NOTCH1 in present lymphomas. Whether IGH/L-NOTCH1 translocations in B-NHL lead to the generation of truncated/activated NOTCH1 proteins, similar to these found in T-ALL, remains to be determined. Particularly interesting is the association of the dic(9;14) with Richter transformation in the first case suggesting that rearrangement of NOTCH1 could be responsible for a rapid progression of the underlied CLL. In the second case of FL, t(9;22) seemed to be associated with the evolution of t(14;18)-positive karyotype. These findings contrast with t(7;9), considered as a primary oncogenic event in development of T-ALL. Further molecular and immunohistochemical investigations of the reported cases are in progress.

scholarly journals Molecular Characterization of Diffuse Large B-Cell Lymphoma Associated to Hepatitis C Virus Infection

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2402-2402
Author(s):  
Roberta Sciarra ◽  
Caterina Cristinelli ◽  
Michele Merli ◽  
Marco Lucioni ◽  
Silvia Zibellini ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Immune Regulation ◽  
Research Funding ◽  
Notch Pathway ◽  
B Cell Lymphoma ◽  
Fish Analysis ◽  
Low Grade ◽  
Advisory Committees

Abstract BACKGROUND. HCV-positive DLBCL has distinct clinical and pathologic characteristics compared to its negative counterpart: patients (pts) are usually older with more frequent splenic and extranodal involvement and elevated LDH. Differently from its clinical hallmarks, the molecular landscape of this pathological entity has been scarcely outlined. METHODS. In this bicentric study, we investigated the clinical and molecular features and outcome of 54 pts with HCV-positive DLBCL. Targeted next generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue biopsies. A core panel probes covering coding exons from 184 genes frequently mutated in mature B cell neoplasms was designed using IDT tool and libraries were prepared using Illumina DNA-prep-with enrichment. Sequencing was performed on Illumina HiSeq 2500. Cluster analysis was performed using LymphGen tool. We also applied fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6. RESULTS. Median age was 71 (33-84; IQR: 61.9-77). Stage was III/IV in 34 pts (63%). Extranodal sites were involved in 21 pts (38%), spleen in 20 pts (37%). LDH was higher than the upper limit in 40 pts (74%). R-IPI was good for 2 pts (4%), intermediate for 24 pts (44%), poor for 28 pts (52%). HPS score was intermediate or high in 33 of 44 assessed pts (75%). A histological low-grade component was identified in 15 pts (27%). Hans algorithm differentiated pts almost equally in GCB (26/50, 52%) and non-GCB (24/50, 48%) subtype. HCV-RNA was detectable in 52 pts (96%) and quantifiable in 43 pts (79%). Of 29 pts assessed, genotype was 1 in 9 (31%), 2 in 16 (55%), 3 in 4 pts (14%). Among 37 pts whose data were available, 11 pts (30%) received direct antiviral agents, 7 pts (19%) received interferon-containing regimen, 19 pts (51%) were not treated for HCV. Twenty-seven pts (50%) received rituximab-enriched protocols, 23 pts (43%) were treated with chemotherapy alone, 1 pt (2%) with surgery alone, 3 pts (5%) were lost to follow up. With a median follow up of 7.7 years (yrs) (IQR: 4.6-10.6), 5-yrs overall survival (OS) (95%CI) was 49.3% (34.1-62.8%) and 5-yrs progression free survival (PFS) (95%CI) was 39.5% (25.5-53.3%). Median OS and PFS were 4.9 and 3.1 yrs, respectively. FISH analysis showed lack of BCL2 (0/19) and MYC translocations (0/15). BCL6 fusions were found in 76% of pts (16/21). NGS showed mutations in 154 of the 184 analyzed genes. The informativity of the panel was 100% with all pts presenting at least one oncogenic variant. Gene mutation frequencies are presented in Fig. 1. The median mutation load (MML) was 13 mutated genes per case (2-32; IQR: 9-16). Most frequently mutated genes were the epigenetic regulators KMT2D, mutated in 23 pts (42.6%), and SETD1B, mutated in 17 pts (31.5%). FAS, PM1 and RERE were mutated in 15 pts each (27.8%). TBL1XR1, BCL11A and SGK1 were mutated in 14 (26%), 13 (24%) and 12 pts (22%), respectively. Considering genes in their specific pathway, 94% of pts harbored mutations in genes involved in epigenetic regulation (MML: 3; range 1-7; IQR: 1.25-4), 90% of pts in apoptosis-related genes (MML: 2; 1-7; IQR: 1-3) and 77% of pts in genes belonging to BCR/NFkB signaling pathway (MML: 2; 1-7; IQR: 1-3). Of note, 56% of pts carried mutations in genes related to immune regulation (MML: 1.7; 1-5; IQR: 1-2) and 25% of pts had mutations within the NOTCH pathway (MML: 1.2; range 1-2). Via the LymphGen 1.0 tool, we classified 26 pts (48%) into 4 genetic clusters: BN2 (11/26, 42%), ST2 (8/26, 31%), MCD (4/26, 15%), EZB (3/26, 12%). Twenty-eight pts (52%) were classified as "others". Among those belonging to BN2 cluster, 7 pts (64%) had a histologically confirmed transformed DLBCL. No significant differences in terms of OS and PFS were identified according to cluster subgroups. CONCLUSIONS. The prevalence of the BN2 cluster and enrichment of mutations of genes involved in NOTCH pathway seem to indicate a preferential marginal-zone origin in HCV-positive DLBCL. In addition, our data confirm the absence of BCL2 translocation in this subset of DLBCL and show a high prevalence of mutated genes within the epigenetic and immune regulation pathways in HCV-positive DLBCL, pointing out their compelling role in the pathogenesis and suggesting potential implications for molecularly targeted therapies. Figure 1 Figure 1. Disclosures Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses.

FOXP1, a Highly Expressed Gene in a Subset of DLBCL, Is Targeted by a Recurrent t(3;14)(p13;q32).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2891-2891
Author(s):  
Iwona Wlodarska ◽  
Peter Vandenberghe ◽  
Peet Nooien ◽  
Anne Hagemeijer ◽  
Peter Marynen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gastric Lymphoma ◽  
Prognostic Significance ◽  
Physiological Role ◽  
B Cell Lymphoma ◽  
Fish Analysis ◽  
Bac Clone ◽  
First Case ◽  
Malt Type Lymphoma

Abstract Chromosomal translocations involving the immunoglobulin heavy chain genes cluster (IGH) at 14q32 have been found in up to 70% of B-non Hodgkin’s lymphoma. These aberrations lead to deregulation of putative oncogenes by their juxtaposition with IGH enhancer elements. So far, more than 20 genes affected by t(14q32) have been identified in B-cell malignancies. The most frequently rearranged genes include BCL1/11q13, BCL2/18q21, BCL6/3q27 and CMYC/8q24. We report here a novel t(3;14)(p13;q32) involving IGH, as shown by FISH, in three lymphoma cases. One of these cases was diagnosed as gastric MALT-type lymphoma, the remaining two cases as diffuse large B-cell lymphoma with a focal nodular growth pattern reminiscent of follicular lymphoma. In order to identify the gene targeted by the t(3;14)(p13;q32) we performed FISH analysis of the first case and narrowed down the breakpoint to RP11-154H23 at 3p13 that showed a split signal on both derivative chromosomes. This BAC clone covers the FOXP1 gene. Using a pair of probes selected for the 5′ and 3′ ends of FOXP1, we demonstrated rearrangement of the gene by dual color FISH in the remaining two cases. An analysis of FOXP1 expression in present cases is being performed. FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that acts as a transcriptional repressor. It is expressed in a wide variety of normal and neoplastic tissues, including lymphomas. FOXP1 has been shown to be expressed in normal activated B-cells using genomic-scale expression profiling, and in B-cells within and outside the germinal center by immunohistochemistry. Its physiological role in lymphocytes, however, is unclear. Recent studies showed that FOXP1 is strongly expressed in a subset of DLBCL. Interestingly, high expression of FOXP1 carries an independent prognostic significance, what suggests a possible role of the gene in the biology of this group of lymphoma. Although genomic rearrangements of FOXP1 have not been demonstrated so far in cancer, rearrangements of other members of FOX gene family in various pathological conditions have been reported. The involvement of FOXP1 in t(3;14)(p13;q32) found in two DLBCL cases indicates that this translocation may underlie a strong expression of FOXP1 in at least part of these lymphomas. Its rearrangement in a case of gastric lymphoma is intriguing, but additional investigations are required to find out whether t(3;14)(p13;q32) is a recurrent aberration in MALT lymphoma. Further molecular, immunophenotypic and clinical studies of the three cases with t(3;14)(p13;q32) are under progress.

Deletions of Chromosomes 6q and 13q, and Trisomy 4 Are the Most Common Cytogenetic Abnormalities in Waldenstrom Macroglobulinemia. Preliminary Results of a Multicentric Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1771-1771
Author(s):  
Florence Nguyen-Khac ◽  
Elise Chapiro ◽  
Sarah Mould ◽  
Carole Barin ◽  
Agnes Daudignon ◽  
...  
Keyword(s):  
B Cell ◽  
Recent Observation ◽  
Partial Trisomy ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Multicentric Study ◽  
Cytogenetic Abnormalities ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Trisomy 12

Abstract The genetic bases of Waldenstrom Macroglobulinemia (WM) are poorly understood. We have studied a cohort of 139 untreated WM patients, enrolled in a prospective randomized trial from the French Cooperative Group on Chronic Lymphocytic Leukemia and Waldenstrom Macroglobulinemia (FCG-CLL/WM), by conventional cytogenetic (CC) and Fluorescence in situ hybridization (FISH). The sex ratio was 2.2M/1F, the average age at inclusion was 66 years [40–85]. The mean percentage of lymphoplasmacytic cells was 53% [8–97]. CC was systematically performed on bone marrow or peripheral blood, and FISH analysis carried out using 7 probes CEP4, CEP12, 13q14, 11q22 ( ATM), 17p13 (TP53), IGH Abbott, 6q21 Q-Biogene, on metaphases and interphase nuclei. Out of 110/137 successful karyotypes, 37% showed clonal abnormalities (9 additional cases had numerical changes of sexual chromosomes). Among abnormal karyotypes, there were 14 (34%) 6q deletions, 5 (12%) trisomy 4/partial trisomy 4, 4 (10%) trisomy 18, 3 (7%) trisomy 12. Using FISH, deletions of 6q21 were observed in 23/86 cases (27%), 13q14 in 12/89 cases (13%), TP53 9/85 cases (11%), ATM 6/81 cases (7%). Trisomy 4 was present in 9/82 cases (11%), and trisomy 12 in 4/86 cases (5%). No rearrangement of IGH was observed in the first 27 analyzed cases. The 6q deletion is the most frequent reported cytogenetic abnormality in WM. We found 27% with deletions of 6q21 (FISH), a low percentage compared to the literature [39–54%]. This could be explained either by the difference in the probe used or by the absence of selection of lymphoplasmacytic cells before cytogenetic analyses. Interestingly, we confirmed our recent observation that trisomy 4 was frequent in WM (12% if partial trisomy 4 was included). Furthermore we observed in this large series a frequent 13q14 deletion (13%). In conclusion, cytogenetic abnormalities in WM differ from those commonly reported in other B-cell neoplasms and confirm the originality of this disease. 6q deletion is frequent compared to CLL or marginal zone lymphoma (MZL) and 13q14 deletion is rare compared to CLL. In our series trisomy 12 is rare compared to atypical-CLL and MZL. We didn’t observe cytogenetic involvement of the IGH locus, which is frequent in multiple myeloma or lymphoplasmocytic lymphoma. Finally trisomy 4 is present in WM but not reported in other B-cell malignancies. Searches for correlations with clinical and other biological parameters are ongoing.

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.

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 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.

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