c-MYC Drives PBK Expression in High-Grade Malignant Lymphomas Through E2F1

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1569-1569
Author(s):  
Fang Hu ◽  
Xianfeng Zhao ◽  
Hongbin Fang ◽  
Ronald Gartenhaus ◽  
Poss Elise Daniela ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Lymphoma ◽  
Rank Correlation ◽  
Correlation Coefficients ◽  
B Cell Lymphoma ◽  
Staining Intensity ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Spearman Rank Correlation ◽  
Spearman Rank

Abstract Abstract 1569 Background: PBK (PDZ-binding kinase) is a serine-threonine kinase that was originally cloned as an interaction partner with the human tumor suppressor hdlg, as an IL-2 inducible gene in cytotoxic T lymphocytes and as an expressed sequence tag in Burkitt's lymphoma (BL) cells. PBK/TOPK mRNA is expressed in normal testicular and embryonic tissues, proliferating neural progenitor cells, various tumor cell lines and in aggressive hematopoietic neoplasms. Previously E2F1 and CREB/ATF were identified as transcriptional regulators of PBK (Leuk Res, 2006). Recently, we reported that PBK interacts with tumor suppressor p53 via its DNA binding domain and modulates its function as a transcription factor (Oncogene, 2010). These lines of evidence point to PBK as a novel oncoprotein with possible relevance as a therapeutic target. c-MYC is the hall mark for Burkitt's lymphoma, and it is highly expressed in various other hematological malignancies. E2F1 is one of the transcriptional targets of c-MYC. The association of PBK expression with aggressive hematologic neoplasms and BL in particular, suggested a possible role of a c-MYC-E2F1-PBK axis in the pathogenesis of hematological malignancies. Study Aim: To investigate the frequency of PBK expression in a larger number of hematopoietic neoplasms and determine whether c-MYC has a role in PBK expression. Methods: Immunohistochemistry for PBK, E2F1 and c-MYC expression on malignant lymphoma tissue microarrays (US Biomax) was conducted. The slides were scored by a blinded hematopathologist (XFZ) according to the following criteria: For staining (0–10), 0= no tumor cells were stained; 1 = 10% tumor cells were stained; 10= 100% tumor cells were stained. For intensity (0–4), 0= no staining; 1= weak; 2=intermediate; 3=strong; 4=very strong. Spearman rank correlation coefficient analysis was used to measure relationships in expression among c-MYC, E2F1 and PBK. To confirm the results from immunohistochemistry assay, effects of c-MYC on expression of E2F1 and PBK were investigated by knocking down c-MYC in Burkitt's lymphoma cell lines and overexpressing c-MYC in HCT116 cells, followed by Western blot analysis for E2F1 and PBK levels. Results: PBK was expressed in 100% of BL samples (N=8), 80% of Diffuse large B-cell Lymphoma (DLBCL) (N=10), 40% of myeloma samples (N=10), 50% of Hodgkins (HL) samples (N=10) but 0/3 Follicular lymphoma (FL) samples, 1/3 T-cell lymphoma samples and 0/4 normal lymph nodes. Among all 44 cases of malignant lymphoma, staining of PBK, E2F1 and c-MYC were significantly positively correlated: Spearman rank correlation coefficient (ρ) between c-MYC and E2F1 is 0.455 (p=0.0028), ρ=0.874 for E2F1 and PBK(p<0.0001), and ρ=0.537 for c-MYC and PBK(p=0.0004); Staining intensity of these three proteins were also significantly positively correlated: ρ=0.407 for c-MYC and E2F1 (p=0.0077), ρ=0.849 for E2F1 and PBK(p<0.0001),and ρ=0.479 for c-MYC and PBK (p=0.0017). In 10 cases of (DLBCL), staining of PBK, E2F1 and c-MYC were significantly positively correlated: Spearman rank correlation coefficients are 0.721, 0.929, and 0.797 for c-MYC and E2F1(p=0.0319), E2F1 and PBK(p<0.0057), c-MYC and PBK(p=0.0177), respectively; In terms of staining intensity of these proteins, Spearman rank correlation coefficients are 0.849, 0.963, and 0.908 for c-MYC and E2F1(p=0.0114), E2F1 and PBK(p=0.0041), c-MYC and PBK(p=0.0068), respectively, in 8 cases of Burkitt's lymphoma, staining intensity of PBK was found to be correlated to that of c-MYC (ρ=0.755, p=0.0492). Gene knockdown experiments in BL2, BJAB, Raji, Daudi cells showed that inhibition of c-MYC expression could downregulate both E2F1 and PBK, whereas overexpression of c-MYC in HCT116 cells increased expression of E2F1 and PBK. Conclusions and Future Directions: PBK protein was highly expressed in a high proportion of Burkitt lymphoma and diffuse large B-cell lymphoma and in a lesser % of Hodgkin lymphoma and myeloma cases, suggesting that PBK is expressed in a relatively high proportion of aggressive hematologic neoplasms. Expression of PBK was correspondent to and subjected to regulation by c-MYC and E2F1 in these lymphomas. These new results in combination with our earlier data as well as the adverse prognostic implications of c-MYC expression in malignant lymphomas suggest that PBK function may be a rational target for novel anti-neoplastic therapeutics. Disclosures: No relevant conflicts of interest to declare.

Identification of Potential Surrogate Endpoints in Randomized Clinical Trials of Aggressive Non-Hodgkin Lymphoma: Correlation of Complete Response, Time-to-Event and Overall Survival Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3699-3699
Author(s):  
Linda M. Lee ◽  
Lisa Wang ◽  
Michael Crump
Keyword(s):  
Cell Lymphoma ◽  
Rank Correlation ◽  
Correlation Coefficients ◽  
Surrogate Endpoints ◽  
Controlled Trials ◽  
Spearman Rank Correlation ◽  
Free Survival ◽  
Spearman Rank ◽  
Aggressive Histology ◽  
Spearman Rank Correlation Coefficient

Abstract Abstract 3699 Poster Board III-635 Background Aggressive histology non-Hodgkin lymphomas (NHLs) are generally treated with curative intent. Establishing appropriate surrogate endpoints for overall survival (OS) may permit more rapid evaluation and approval of new agents for aggressive NHL. Treatment failure endpoints including event-free survival (EFS) or progression-free survival (PFS) permit earlier reporting of results, but their ability to predict OS is unknown. The purpose of this study is to correlate different efficacy endpoints with the goal of identifying an appropriate surrogate endpoint for OS. Methods Randomized controlled trials (RCTs) of previously untreated aggressive histology NHL published between 1990-2009 were identified through a systematic literature search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Eligible RCTs included at least 2-arms comparing different systemic treatments with ≥100 patients/arm. Studies investigating the effect of autologous stem-cell transplant and those exclusively involving T-cell lymphoma, mantle cell lymphoma or HIV-associated lymphoma were excluded. Baseline characteristics, design, treatment arms, efficacy endpoints, and results were extracted from each published RCT. Reported survival endpoints were defined as PFS, EFS, or OS according to established (ie: per protocol) definitions in the International Working Group Revised Response Criteria for Lymphoma. Absolute differences in efficacy endpoints were determined and nonparametric Spearman rank correlation coefficients were calculated to determine the association between differences in: 1) CR and each of EFS, PFS and OS and 2) EFS or PFS and OS. Results Thirty-eight RCTs were identified representing 85 treatment arms and 16,103 patients. The median follow up was 55 months (range 20-108). The most commonly used primary endpoint was OS (55%) followed by EFS (32%), but use of CR as a primary endpoint was infrequent (5%). Differences in CR strongly correlated with differences in 3-yr EFS with a Spearman rank correlation coefficient of 0.88 (95% CI: 0.57 to 0.97). The Spearman rank correlation coefficients between differences in CR and differences in 3-yr PFS and 5-yr OS were 0.62 (95% CI: 0.21 to 0.84) and 0.50 (95% CI, 0.23 to 0.74), respectively. Differences in intermediate endpoints, 3-yr PFS or EFS, were high correlated with differences in 5 yr OS with a Spearman rank correlation coefficient of 0.90 (95%CI, 0.73-0.96). Similarly strong correlations were noted when 3-yr PFS and 3-yr EFS were each correlated with 5-yr OS separately. Linear regression determined that a 10% improvement in CR is estimated to correspond with a 9±1% improvement in 3-yr EFS and that a 10% improvement in 3-yr EFS or PFS would predict for a 7±1% improvement in 5-yr OS. Conclusions In RCTs of initial treatment for aggressive NHL, improvements in 3-yr EFS/PFS are highly correlated with improvements in 5-yr OS. Changes in CR rates are a strong predictor for changes in 3-yr EFS, but not for changes in 5-yr OS. This may inform future trial design since EFS or PFS appear to be appropriate surrogate endpoints for OS in this patient population. Disclosures: No relevant conflicts of interest to declare.

Difference of seasonal variation between glycated albumin and glycated haemoglobin

2018 ◽  
Vol 55 (5) ◽  
pp. 583-587 ◽  
Author(s):  
Karin Tanaka ◽  
Shu Meguro ◽  
Masami Tanaka ◽  
Junichiro Irie ◽  
Yoshifumi Saisho ◽  
...  
Keyword(s):  
Seasonal Variation ◽  
Plasma Glucose ◽  
Seasonal Variations ◽  
Glycated Albumin ◽  
Rank Correlation ◽  
Correlation Coefficients ◽  
Glycated Haemoglobin ◽  
Spearman Rank Correlation ◽  
Spearman Rank ◽  
Average Temperature

Background Glycated albumin reflects 2–3-week glycaemic controls, and in addition to glycated haemoglobin, it has been used as a glycaemic control indicator. We presumed that glycated albumin also has seasonal variations and is related to temperature, similar to glycated haemoglobin. Methods The subjects were diabetic outpatients from April 2007 to March 2013. This resulted in the enrolment of 2246 subjects and the collection of a total of 53,968 measurements. Mean glycated haemoglobin, glycated albumin, and plasma glucose were calculated for each month over six years. The associations of the measures with each other and the average temperature for each month in Tokyo were assessed using Spearman rank correlation coefficients. Results Plasma glucose was highest in January and lowest in May. Glycated haemoglobin was highest in March and lowest in September. Glycated albumin was highest in May and lowest in December. Glycated albumin tended to have a disjunction with plasma glucose in winter. Glycated haemoglobin had seasonal variation, but glycated albumin did not. Plasma glucose and glycated haemoglobin showed significant negative correlations with temperature (rs = −0.359, P < 0.001, rs = −0.449, P < 0.001, respectively), but glycated albumin did not. However, glycated albumin was inter-correlated with plasma glucose (rs = 0.396, P < 0.001) and glycated haemoglobin (rs = 0.685, P < 0.001), and glycated haemoglobin was inter-correlated with plasma glucose (rs = 0.465, P < 0.001). Conclusion Glycated albumin and glycated haemoglobin showed different seasonal variations from each other over the six-year study period. Thus, further studies to identify factors that contribute to glycated albumin are needed.

scholarly journals Burkitt’s Lymphoma and B-Cell Lymphoma Unclassifiable With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt’s Lymphoma in Patients With HIV: Outcomes in a South African Public Hospital

2017 ◽  
Vol 3 (3) ◽  
pp. 218-226 ◽  
Author(s):  
Gerhard Sissolak ◽  
Matthew Seftel ◽  
Thomas S. Uldrick ◽  
Tonya M. Esterhuizen ◽  
Nooroudien Mohamed ◽  
...  
Keyword(s):  
South Africa ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
High Dose ◽  
Baseline Serum ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Purpose Burkitt’s lymphoma (BL) is a common HIV-associated lymphoma in South Africa. B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma (BL/DLBCL) also occurs in HIV infection. Outcomes of HIV-infected patients with BL or BL/DLBCL in a resource-constrained setting are not defined. Methods We performed a retrospective study of HIV-positive patients with BL or BL/DLBCL treated from 2004 to 2012 with curative intent at a publically funded academic medical center in South Africa. Differences between BL and BL/DLBCL, survival outcomes, and factors associated with survival were analyzed. Results There were 35 patients with either HIV-associated BL (24) or BL/DLBCL (11) who met study criteria. Median CD4+ T-lymphocyte count at lymphoma diagnosis was 188 cells/μL (range, 10 to 535 cells/μL). Patients with BL/DLBCL were significantly older and had less bone marrow involvement and lower baseline serum lactase dehydrogenase than patients with BL. Eighty-nine percent of patients presented with advanced disease, and 25% had baseline CNS involvement. Chemotherapy regimens consisted of cytoreduction with low-dose cyclophosphamide, vincristine, and prednisone followed by induction with vincristine, methotrexate, cyclophosphamide, doxorubicin and prednisone (LMB 86; 57%); hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine (hyper-CVAD; 20%); cyclophosphamide, doxorubicin, vincristine, and prednisone and high-dose methotrexate with leucovorin rescue on day 10 with accompanying prophylactic IT chemotherapy (Stanford regimen; 14%); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-like; 9%) regimens. Twenty-three patients received CNS treatment or prophylaxis, and 31 received concurrent combination antiretroviral therapy. Two-year overall survival was 38% (95% CI, 22% to 54%) and 2-year event-free survival was 23% (95% CI, 11% to 38%), with no difference between histologic subtypes. Common causes of death were infection (41%) and CNS disease progression or systemic relapse (41%). Conclusion Cure of HIV-associated BL and BL/DLBCL with intensive regimens is possible in resource-limited settings, but lower toxicity regimens, improved CNS prophylaxis, and increased resources for supportive care are required.

Chloroquine Inhibits Autophagy, Enhances p53-Dependent Apoptosis, and Delays Tumor Recurrence in a Mouse Model of B Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2421-2421 ◽  
Author(s):  
Ravi K. Amaravadi ◽  
Duonan Yu ◽  
Andrei Thomas-Tikhonenko ◽  
Craig B. Thompson
Keyword(s):  
Mouse Model ◽  
Fusion Protein ◽  
B Cell ◽  
Nuclear Localization ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Recurrent Tumors

Abstract Burkitt’s lymphoma is an example of an aggressive B cell neoplasm characterized by overexpression of the c-myc oncogene and frequent inactivation of the tumor suppressor gene p53. A non-transgenic mouse model of Burkitt’s lymphoma was generated by retroviral transduction of the human c-myc gene into bone marrow cells derived from the p53-estrogen receptor (p53ER) knock-in mouse. The resulting myc/p53ER cells produce an aggressive B cell lymphoma when injected subcutaneously into the flanks of syngeneic mice. When tumor-bearing mice are treated with tamoxifen intraperitoneally, the p53ER fusion protein is targeted to the nucleus where p53-dependent apoptosis can take place. On successive in vivo passages, cells develop the ability to survive p53 activation and escape p53ER-dependent apoptosis despite tamoxifen treatment and nuclear localization of the p53ER fusion protein. We hypothesized that cells resistant to p53-dependent apoptosis utilize autophagy as an essential survival mechanism. Thus, these tumors could be sensitive to chloroquine, a lysosomotropic inhibitor of autophagy that has been used extensively in humans as an antimalarial and for the treatment of rheumatoid arthritis. Daily intraperitoneal chloroquine or hydroxychloroquine treatment of mice bearing myc/p53ER tumors in the absence of tamoxifen resulted in a delay in tumor growth. When tamoxifen was added to induce nuclear localization of p53ER, mice that received tamoxifen plus chloroquine had a complete tumor response while mice that received tamoxifen plus saline had transient tumor shrinkage followed quickly by regrowth. Tamoxifen plus chloroquine treatment enhanced the expression of p53-dependent target genes and increased caspase activation compared to tamoxifen plus saline treatment. A higher percentage of cells in tumors treated with tamoxifen plus chloroquine underwent apoptosis compared to tumors treated with tamoxifen plus saline. Moreover, tumors that recurred in the mice treated with daily tamoxifen plus chloroquine did so after a significantly longer latency period then mice treated with tamoxifen plus saline. Recurrent tumors showed loss of expression of p53 target genes. Electron microscopy of recurrent tumors confirmed the accumulation of vacuoles in chloroquine treated tumors compared to controls, suggesting inhibition of lysosome function leads to the accumulation of ineffective autophagic vacuoles. These results indicate that inhibiting autophagy with lysosomotropic chloroquine derivatives could be a useful therapeutic addition to treatment regimens for aggressive B cell lymphomas.

Concurrent Chromosomal Alterations at 3q27, 8q24 and 18q21 in An Atypical Form of Burkitt’s Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5268-5268
Author(s):  
Majdi SM Hamarshi ◽  
Maha abu Kishk ◽  
Mahmoud Mahafzah ◽  
Jami Walloch
Keyword(s):  
Bone Marrow ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
High Grade ◽  
Surface Immunoglobulin ◽  
Cell Neoplasm

Abstract Introduction: Chromosomal translocations are common in non-Hodgkin’s lymphomas (NHL), most frequently involving the genes bcl-2 in the t(14;18) of follicular lymphoma (FL), c-myc in the t(8;14) of Burkitt’s lymphoma (BL) and bcl-6 in the t(3;14) of follicular or diffuse large B-cell (DLBC) lymphoma. We report the clinical features, pathology and genetic findings in an exceedingly rare case of Burkitt’s lymphoma that showed concurrent involvement of these three chromosomal loci. Case Report: This is a 65 year old Caucasian female who presented with a rapidly growing right supraclavicular lymph node over a few weeks. FNA biopsy showed typical morphology of Burkitt’s lymphoma. Similar morphologic features were found on the bone marrow biopsy. There was widespread disease with no CNS involvement. Flow cytometry from peripheral blood and immunohistochemistry on the cellblock showed B-cell phenotype positive for CD 10, CD19, CD20 (negative CD20 by immunohistochemistry), HLA-DR, cytoplasmic CD79a, and negative for CD34 and TdT. The interesting finding was the lack expression of surface or cytoplasmic immunoglobulin and expression of weak Bcl-6. Almost 90–95% expressed Ki67. The cytogenetic analysis reportedly demonstrated a complex karyotype t(3;8;14), and t(14;18) involving c-myc (8q24), bcl-2 (18q21), and bcl-6 (3q27). After 7 cycles of hyper CVAD-R she had bone marrow biopsy which showed residual disease. She also had a biopsy confirmed relapse as left arm nodule and left leg nodular infiltrate at 8 and 12 months form the diagnosis, respectively. Discussion: This is a complex case of high grade B-cell lymphoma with morphology suggestive of Burkitt’s lymphoma. However the classification was challenging by the lack of surface immunoglobulin expression that might be expected in mature B-cell neoplasm “DLBCL, FL”, and the lack of TdT and CD34 that might be expected in precursor B-cell neoplasm “BL”. The diagnosis was highly dependent on the cytogenetic findings, which was significant for the presence of t(8;14) albeit in a three way translocation t(3;8;14), and t(14;18) involving c-myc (8q24), bcl-2 (18q21), and bcl-6 (3q27). The lymphoma was therefore described as “Burkitt’s transformation”. This is a rare translocation pattern, but has been described in follicular lymphoma, grade 3; diffuse large cell lymphoma; and Burkitt’s lymphoma. Conclusion: BL might lack surface immunoglobulin expression making the diagnosis of high grade B-cell lymphoma challenging if based on the morphology and immunophenotyping alone. The cytogentetic findings better delineate sub-types of lymphoma. Molecular evidence of multiple oncogene deregulations, especially when involving the c-myc gene, appears to be associated with a dire clinical outcome.

Effective treatment of aggressive B-cell lymphomas by downregulated NIK-induced noncanonical NF-κB pathway activation through inhibition of BAFF.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13554-e13554
Author(s):  
Sung Hsin Kuo ◽  
Li-Tzong Chen ◽  
Kun-Huei Yeh ◽  
Hui-Jen Tsai ◽  
Hsiao-Wei Lee ◽  
...  
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Luciferase Assay ◽  
Aggressive B Cell Lymphoma

e13554 Background: We recently reported that autocrine BAFF (B cell–activating factor belonging to the TNF family) signal transduction pathway contributes to H. pylori-independent growth of gastric diffuse large B-cell lymphoma (DLBCL) (Blood 2008;112:2927-34; Ann Hematol 2010;89:431-6). In this study, we sought to investigate whether activation of BAFF signaling pathway can promote the survival and proliferation of aggressive B-cell lymphoma. Methods: Seven aggressive NHL cell lines (EBV-negative Burkitt’s lymphoma (Ramos), EBV-positive Burkitt’s lymphoma (Raji), EBV-negative undifferentiated lymphoma (MC116), activated B cell (ABC)-like DLBCL (OCI-Ly3, OCI-Ly10), and germinal center B cell (GCB)-like DLBCL (OCI-Ly7, and Pfeiffer) were used in this study. Cell cycle was analyzed by flow cytometry. The DNA-binding activity of NF-kB was determined by the luciferase assay. Expression of non-canonical NF-κB signatures-related proteins (BAFF, BAFF-R, NIK, cIAP1, TRAF2, cIAP1/2, TRAF3, IKKa, p100, p52 and RelB, BCL10, BCL3, and STAT3) was assessed by immunoblotting. Results: Our results showed that in GCB-DLBCL cell lines, activation of BAFF induced recruitment and degradation of TRAF3, which resulted in NIK kinase accumulation, BCL10 Ser138 phosphorylation, IKKa phosphorylation, and NF-kB p100 processing, thereby resulting in continuous activation of non-canonical NF-kB pathway. This phenomenon also resulted in BCL3 nuclear translocation and STAT3 activation, and subsequently activated STAT3 downstream-regulated genes (BCL2, survivin, and cyclin D1). Furthermore, we found that inhibition of BAFF by short hairpin RNA (shRNA) suppressed the growth of ABC-DLBCL cells and Burkitt lymphoma cells through the down-regulation of BAFF/BAFF-R/TRAF3/NIK/BCL3/NF-kB signaling pathway. Conclusions: Our results indicate that constitutive BAFF signaling activates NIK-induced non-canonical NF-kB signaling pathway in aggressive B-cell lymphoma, and inhibition of BAFF is particularly effective in the treatment of this subgroup of tumors.

scholarly journals Pediatric Burkitt's Lymphoma and Diffuse B-Cell Lymphoma: Are Surveillance Scans Required?

2013 ◽  
Vol 31 (3) ◽  
pp. 253-257 ◽  
Author(s):  
H.M. Eissa ◽  
C.E. Allen ◽  
K. Kamdar ◽  
S. Simko ◽  
P. Goradia ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Diffuse B Cell Lymphoma
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