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.

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.

IgG-Secreting B-Cell Lymphoplasmocytoid Leukaemia : Molecular Characterization of Igh Rearrangements.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1778-1778
Author(s):  
Laurence Lode ◽  
Surinder S. Sahota ◽  
Soraya Wuilleme ◽  
Steven Richebourg ◽  
Marion Eveillard ◽  
...  
Keyword(s):  
B Cell ◽  
Elevated Serum ◽  
Chromosomal Translocation ◽  
Memory Cell ◽  
Fish Analysis ◽  
Cell Repertoire ◽  
Igh Locus ◽  
B Cell Repertoire ◽  
Vh Genes

Abstract Purpose : Elevated serum M component of IgG isotype is typically associated with multiple myeloma (MM). However, our group has previously reported cases with an elevated serum monoclonal IgG and a leukaemic B-cell lymphoplasmocytoid lymphoma (LPL) similar to Waldenstrom’s macroglobulinaemia (WM). The aim of this study was to extend analysis of IgH locus events in a larger series of IgG-secreting LPL. Patients and Methods : We investigated 20 patients with an elevated serum monoclonal IgG (>20g/l) and LPL (IgG-LPL). Morphological classification and immunophenotyping analysis were performed at diagnosis (serum IgG>4 g/l, CD19+ cells >30%, presence of lymphoplasmocytoid cells in blood and/or bone marrow). Histological classification and FISH analysis were performed when possible to further characterize those cases. Analysis of VH genes was carried out from RNA with VHLeader and CH primers. 14 patients were examined for both IgG and IgM transcripts; VH-Cμ and VH-Cg transcripts could be compared in 9 patients. Results : Of 25 Ig VH rearrangement sequences, 23 were functional and expressed in each case. VH3 family members appeared to be over-represented (19/21 patients (90.5%) as compared to 40/71 (56.3%) in normal B-cell repertoire (1). VH3-23 was the most frequently used segment (10/21 patients) and is frequently utilized in normal B-cells. IgG-LPL JH family use resembled the normal B-cell repertoire (predominance of JH4 and JH6 segments). The median CDR3 length was 10 amino acids [5–19]. However, and in contrast with features seen in other leukaemia, there was no evidence of homologous CDR3 motifs. All VH genes revealed highly somatically mutated sequences, with a median mutation rate 8.8% [0.7 – 11.1%] (IMGT database(2)). We compared pre (VH-Cμ) and post-switch (VH-Cg) transcripts, and 4/9 patients had identical clonally-derived sequences, and two 2/9 had divergent sequences. Interpretation and conclusion : This intended study of IgG-LPL reveals consistent features that argue for common origins of IgG-LPL with Waldenstrom’s macroglobulinemia. One feature is extensive somatic mutations in VH genes, suggesting origins from a cell that may have undergone successive rounds of mutation. Patterns of mutations in pre-and post-switched clonally derived sequences suggest that the final neoplastic event has occurred in a IgM+ memory cell undergoing isotype switch. However, no aberrant chromosomal translocation accrue at the IgH locus, as apparent from FISH data. This indicates that, unlike in typical MM, switch activity does not generate 14q32 abnormalities nor that such lesions play a role in the pathogenesis of LPL. Extensive mutations are also seen in VH genes in WM, and there is evidence that WM cells can undergo class switch events in vivo. In this tumor, switching occurs at a low subclonal level in some cells, which in rare cases can lead to the emergence of a dual population of clonally identical IgM and IgG expressing WM tumor cells at a later stage of disease (7). In typical WM, 14q32 abnormalities are also generally not seen. These data suggest that IgG-LPL and WM could be two variants of the same entity, with IgG-LPL exposed to persistent switch stimuli following transformation.

The BCL11 gene family: involvement of BCL11A in lymphoid malignancies

Blood ◽  
2001 ◽  
Vol 98 (12) ◽  
pp. 3413-3420 ◽  
Author(s):  
Ed Satterwhite ◽  
Takashi Sonoki ◽  
Tony G. Willis ◽  
Lana Harder ◽  
Rachael Nowak ◽  
...  
Keyword(s):  
B Cells ◽  
Gene Family ◽  
B Cell ◽  
Family Involvement ◽  
Cpg Island ◽  
Rare Event ◽  
Fetal Brain ◽  
Chromosomal Translocation ◽  
Lymphocytic Leukemia ◽  
Lymphoid Malignancies

Abstract Many malignancies of mature B cells are characterized by chromosomal translocations involving the immunoglobulin heavy chain(IGH) locus on chromosome 14q32.3 and result in deregulated expression of the translocated oncogene. t(2;14)(p13;q32.3) is a rare event in B-cell malignancies. In contrast, gains and amplifications of the same region of chromosome 2p13 have been reported in 20% of extranodal B-cell non-Hodgkin lymphomas (B-NHL), in follicular and mediastinal B-NHL, and in Hodgkin disease (HD). It has been suggested that REL, an NF-κB gene family member, mapping within the amplified region, is the pathologic target. However, by molecular cloning of t(2;14)(p13;q32.3) from 3 cases of aggressive B-cell chronic lymphocytic leukemia (CLL)/immunocytoma, this study has shown clustered breakpoints on chromosome 2p13 immediately upstream of a CpG island located about 300 kb telomeric of REL. This CpG island was associated with a Krüppel zinc finger gene (BCL11A), which is normally expressed at high levels only in fetal brain and in germinal center B-cells. There were 3 major RNA isoforms ofBCL11A, differing in the number of carboxy-terminal zinc fingers. All 3 RNA isoforms were deregulated as a consequence of t(2;14)(p13;q32.3). BCL11A was highly conserved, being 95% identical to mouse, chicken, and Xenopus homologues.BCL11A was also highly homologous to another gene(BCL11B) on chromosome 14q32.1. BCL11Acoamplified with REL in B-NHL cases and HD lymphoma cell lines with gains and amplifications of 2p13, suggesting thatBCL11A may be involved in lymphoid malignancies through either chromosomal translocation or amplification.

scholarly journals Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL

2020 ◽  
Vol 4 (3) ◽  
pp. 560-572 ◽  
Author(s):  
Rakesh Awasthi ◽  
Lida Pacaud ◽  
Edward Waldron ◽  
Constantine S. Tam ◽  
Ulrich Jäger ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Statistical Significance ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Extrinsic Factors ◽  
Cellular Kinetics

Abstract The anti-CD19 chimeric antigen receptor (CAR)–T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

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.

Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies

2017 ◽  
Vol 51 (5) ◽  
pp. 410-416 ◽  
Author(s):  
Amber C. King ◽  
Tim J. Peterson ◽  
Troy Z. Horvat ◽  
Mabel Rodriguez ◽  
Laura A. Tang
Keyword(s):  
Adverse Effect ◽  
B Cell ◽  
Data Extraction ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Lymphoid Malignancies ◽  
Oral Agents ◽  
American Society

Objective: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. Data Sources: A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. Study Selection/Data Extraction: Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. Data Synthesis: Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration–approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. Conclusion: Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

Pattern of Mir-155 and PU.1 Expression in CLL/SLL and Aggressive Lymphomas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4600-4600
Author(s):  
Tomas Stopka ◽  
Karin Vargova ◽  
Hana Huskova ◽  
Pavel Burda ◽  
Nikola Curik ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Peripheral T Cell Lymphoma ◽  
Lymphoid Malignancies ◽  
Mantle Cell ◽  
Prognostic Groups ◽  
Nfkb Pathway

Abstract Abstract 4600 MicroRNA miR-155 represents a candidate pathogenic factor in chronic lymphocytic leukemia (CLL) and lymphomas (Eis PS, et al. 2005, Fulci V, et al. 2007, Calin GA, et al. 2005, Kluiver J, et al. 2005, Metzler M, et al. 2004, van den Berg A, et al. 2003., Vargova K. et al 2011). In diffuse large B-cell lymphoma (DLBCL) expression of miR-155 was associated with NFkB pathway (Rai et al., 2008). In addition, increased miR-155 levels were associated with more aggressive (Activated B-cell like) DLBCL (Eis et al. 2005). The targets of up-regulated miR-155 apparently include a key hematopoietic transcription factor PU.1. Down-regulation of PU.1 represents an important and critical step for both myeloid as well as lymphoid tumorigenesis. We herein found the increased levels of miR-155 coupled with downregulation of its target PU.1 are frequent events in B cells of a vast majority of CLL patients (N=169). To advance understanding of miR-155 and PU.1 in lymphoid malignancies we studied lymph node biopsies derived from patients with lymphomas. We show that increased miR-155 levels are also found in DLBCL (N=31, P < 0.0001), Hodgkin lymphoma (HL, N=22, P < 0.0001), follicular lymphoma (FL, N=23, P < 0.001), small lymphocytic lymphoma (SLL, N=12, P < 0.01), and marginal zone lymphoma (MZL, N=11, P < 0.01). The miR-155-overexpressing tumors display downregulation of PU.1. In contrast, peripheral T cell lymphoma (T-NHL, N=6) and mantle cell lymphoma (MCL, N=7) expressed miR-155 and PU.1 comparably as control lymph nodes. Our data indicate that expression pattern of miR-155 and its target PU.1 represents a hallmark of some but not all lymphoid malignancies. Interestingly, the miR-155/PU1 levels vary substantially within each diagnosis, therefore, our aim is to further analyze the occurrence of this relationship in different prognostic groups and analyze the clinical outcome as well. (Grants: NT10310-3/2009 & NT11218-6/2010, MPO FR-TI2/509, GAUK251135 82210 & 251070 45410, SVV-2011-262507) Disclosures: No relevant conflicts of interest to declare.

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 &gt; 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 &lt; 3. The IgVH genes were unmutated in 9/11 cases. The time to treatment was &lt; 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 &lt; 3, which could be of poor prognosis, based on progressive disease and unmutated status.

scholarly journals Association of bcl-1 rearrangements with lymphocytic lymphoma of intermediate differentiation

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2086-2090 ◽  
Author(s):  
LJ Medeiros ◽  
JH Van Krieken ◽  
ES Jaffe ◽  
M Raffeld
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Chromosomal Translocation ◽  
B Cell Lymphoma ◽  
Distinct Type ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Low Grade ◽  
Chromosome 11 ◽  
Follicular Lymphomas

Abstract Previous studies using classical cytogenetics have demonstrated the presence of the t(11;14) (q13;q32) chromosomal translocation in some cases of lymphocytic lymphoma of intermediate differentiation (IDL), a distinct type of low grade B-cell lymphoma. This finding suggested that the bcl-1 region (located at band q13 of chromosome 11) might be involved in this neoplasm. Using a genomic probe from the major breakpoint area of the bcl-1 locus, we identified rearrangements of the bcl-1 region in 10 of 19 cases, 2 of which comigrated with a rearranged allele of the immunoglobulin heavy chain gene joining region. In contrast, bcl-1 rearrangements were not found in other types of low grade B-cell lymphoma, specifically in 36 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 27 cases of follicular lymphoma (FL). To further assess the molecular pathology of IDL, we analyzed these cases for rearrangements of the bcl-2 proto- oncogene, which is associated primarily with follicular lymphomas. None of the 19 cases of IDL had rearrangements. Furthermore, none of the 36 cases of CLL/SLL showed bcl-2 rearrangements, whereas, as expected, 21 of 27 cases of FL had rearrangements of the bcl-2 locus. Our findings demonstrate an association between a rearranged bcl-1 region with approximately 50% of IDLs and suggest that abnormalities of this locus may be important in the pathogenesis of IDL.

scholarly journals Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Isha Kapoor ◽  
Yue Li ◽  
Arishya Sharma ◽  
Huayuan Zhu ◽  
Juraj Bodo ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Nuclear Export ◽  
Acquired Resistance ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Nuclear Accumulation ◽  
Lymphoid Malignancies ◽  
Ibrutinib Resistance ◽  
Induced Apoptosis

AbstractChronic activation of the Bruton’s tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling is a hallmark of many B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Ibrutinib, an FDA approved, orally administered BTK inhibitor, has demonstrated high response rates, however, complete responses are infrequent and acquired resistance to BTK inhibition can emerge. In this study, we generated ibrutinib-resistant (IB-R) cell lines by chronic exposure of CLL and activated B-cell (ABC)-DLBCL cells to ibrutinib in order to investigate the mechanism of acquired resistance to ibrutinib. IB-R cell lines demonstrated downregulation of FOXO3a and PTEN levels and activation of AKT, with their levels being low in the nuclei of resistant cells in comparison to the sensitive counterparts. Inhibition of PI3K and AKT using idelalisib and MK2206, respectively increased ibrutinib-induced apoptosis in IB-R cells by downregulation of pAKT473 and restoring FOXO3a levels, demonstrating the importance of these cell survival factors for ibrutinib-resistance. Notably, the exportin 1 inhibitor, selinexor synergized with ibrutinib in IB-R cells and restored nuclear abundance of FOXO3a and PTEN, suggesting that nuclear accumulation of FOXO3a and PTEN facilitates increase in ibrutinib-induced apoptosis in IB-R cells. These data demonstrate that reactivation of FOXO3a nuclear function enhances the efficacy of ibrutinib and overcomes acquired resistance to ibrutinib. Together, these findings reveal a novel mechanism that confers ibrutinib resistance via aberrant nuclear/cytoplasmic subcellular localization of FOXO3a and could be exploited by rational therapeutic combination regimens for effectively treating lymphoid malignancies.

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