KLF4 is a tumor suppressor in B-cell non-Hodgkin lymphoma and in classic Hodgkin lymphoma

The transcription factor KLF4 may act both as an oncogene and a tumor suppressor in a tissue-depending manner. In T- and pre-B-cell lymphoma, KLF4 was found to act as tumor suppressor. We found the KLF4 promoter methylated in B-cell lymphoma cell lines and in primary cases of B-cell lymphomas, namely, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, and in classic Hodgkin lymphoma (cHL) cases. Promoter hypermethylation was associated with silencing of KLF4 expression. Conditional overexpression of KLF4 in Burkitt lymphoma cell lines moderately retarded proliferation, via cell-cycle arrest in G0/G1. In the cHL cell lines, KLF4 induced massive cell death that could partially be inhibited with Z-VAD.fmk. A quantitative reverse-transcribed polymerase chain reaction array revealed KLF4 target genes, including the proapoptotic gene BAK1. Using an shRNA-mediated knock-down approach, we found that BAK1 is largely responsible for KLF4-induced apoptosis. In addition, we found that KLF4 negatively regulates CXCL10, CD86, and MSC/ABF-1 genes. These genes are specifically up-regulated in HRS cells of cHL and known to be involved in establishing the cHL phenotype. We conclude that epigenetic silencing of KLF4 in B-cell lymphomas and particularly in cHL may favor lymphoma survival by loosening cell-cycle control and protecting from apoptosis.

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The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines

Frontiers in Oncology ◽

10.3389/fonc.2019.01301 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Gro Elise Rødland ◽

Katrine Melhus ◽

Roman Generalov ◽

Sania Gilani ◽

Francesco Bertoni ◽

...

Keyword(s):

Cell Cycle ◽

B Cell ◽

Cell Lines ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoma Cell ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Cell Cycle Kinase

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Combination of Enzastaurin, a PKC Inhibitor, and Revlimid ® has Synergistic Activity In Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v116.21.4905.4905 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4905-4905 ◽

Cited By ~ 1

Author(s):

Stefano Sacchi ◽

Maria Cosenza ◽

Monica Civallero ◽

Giulia Grisendi ◽

Erika Road ◽

...

Keyword(s):

B Cell ◽

Cell Line ◽

Hodgkin Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoma Cell ◽

Indolent Lymphoma ◽

Non Hodgkin Lymphoma

Abstract Abstract 4905 A curative treatment does not exist for indolent lymphoma and eventually patients die for progression and complications related to their disease. Thus, there is a need of new less toxic and more active treatment. Enzastaurin, a novel targeted agent, inhibits PKC-β by interacting competitively as its ATP-binding site. Several studies have shown that enzastaurin exhibits growth inhibiting effects on a wide array of cultured human tumour cells. Revlimid ® (lenalidomide), an oral immunomodulatory drug, have shown antineoplastic activity in various tumours, including multiple myeloma (MM), myelodysplastic syndrome (MDS), B-CLL, renal-cell carcinoma and prostate cancer and it is approved for the treatment of patients with MM and MDS bearing a deletion 5q. In the present research, we demonstrate that Revlimid ® alone induce G0/G1 arrest in WSU-NHL cell line, but not apoptosis. This would suggest that, in vitro, Revlimid ® has more a cytostatic than a cytotoxic effect in this cell line. Further, we have demonstrated that the combination of doses as low as 1 mM of Enzastaurin and Revlimid ® exerts, in vitro, a strong synergistic anti lymphoma activity. We also have showed that the combination decreases viability and induce apoptosis in B-cell lymphoma cell lines and peripheral blood mononuclear cells (PBMCs) from follicular lymphoma (FL) patients. The combination has no effect on normal PBMC and suppresses cell proliferation of B-cell lymphoma cell lines when co-cultured with bone marrow stromal cells (BMSCs) in a system that mimics the BM microenvironment. The combination induces a significantly higher rate of apoptosis in comparison with these caused by each agents utilized alone, as showed by flow cytometry. The combination activates both the extrinsic and intrinsic pathways of apoptosis resulting in caspase-8, caspase-9, caspase-3 and PARP cleavage. Furthermore, we have evaluated whether the combination has the ability to trigger apoptosis through BAD and we have showed its ability to activate BAD. Further, we have demonstrated that the combination decreases the expression of phosphorylated AKT and of some AKT downstream targets such as GSK-3β, m-TOR and p70S6. In addition, we have found that the combination reduces the activation of phosphorylated MAPK and of the downstream effector p90RSK. The MAPK signaling pathways have a multiple roles in natural processes such as cell growth, differentiation, and apoptosis. Taken together, these observations suggest that interrupting the PI3K/AKT and MAPK pathways is a promising therapeutic strategy against B-cell lymphoma cell lines. Therefore, these preclinical data, together with promising results obtained with Revlimid ® in the treatment of non-Hodgkin lymphoma, provide the rationale for evaluating the combination of Enzastaurin and Revlimid ® in the treatment of indolent lymphoma. These compounds, with a favourable toxicity profile, are not classic chemotherapeutic agents causing severe side effects and could be considered an example of a new innovative attempt of an anti-cancer “soft treatment”. Disclosures: No relevant conflicts of interest to declare.

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Cell cycle effects of CDK 4/6 inhibitor PD 0332991 in diffuse large B-cell lymphoma cell lines in vitro.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.8061 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 8061-8061

Author(s):

H. A. Eradat ◽

M. A. Eckardt ◽

E. Dorfman ◽

H. Hamidi ◽

C. Ginther ◽

...

Keyword(s):

Cell Cycle ◽

B Cell ◽

Cell Lines ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoma Cell ◽

Large B Cell Lymphoma ◽

Large B Cell

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DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene

Oncogene ◽

10.1038/sj.onc.1201172 ◽

1997 ◽

Vol 15 (4) ◽

pp. 403-407 ◽

Cited By ~ 131

Author(s):

Joseph L Kissil ◽

Elena Feinstein ◽

Ofer Cohen ◽

Peter A Jones ◽

Yvonne C Tsai ◽

...

Keyword(s):

Tumor Suppressor ◽

B Cell ◽

Tumor Suppressor Gene ◽

Cell Lines ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Suppressor Gene ◽

Lymphoma Cell ◽

Dap Kinase

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TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma

Journal of Experimental Medicine ◽

10.1084/jem.20090528 ◽

2009 ◽

Vol 206 (5) ◽

pp. 981-989 ◽

Cited By ~ 333

Author(s):

Roland Schmitz ◽

Martin-Leo Hansmann ◽

Verena Bohle ◽

Jose Ignacio Martin-Subero ◽

Sylvia Hartmann ◽

...

Keyword(s):

Tumor Suppressor ◽

B Cell ◽

Hodgkin Lymphoma ◽

Tumor Suppressor Gene ◽

Cell Lines ◽

Target Genes ◽

Zinc Finger Protein ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Suppressor Gene

Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor κB (NF-κB). NF-κB activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus–positive (EBV+) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV− cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-κB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-κB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-κB activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV− than EBV+ cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.

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An Interesting Case Report of A Concurrent Classic Hodgkin Lymphoma and Gray Zone Lymphoma in the Mediastinum

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.240 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S110-S110

Author(s):

B Mai ◽

J Huddin ◽

Z Hu

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Mediastinal Mass ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Gray Zone ◽

Large B Cell Lymphoma ◽

Classic Hodgkin Lymphoma ◽

Atypical Cells ◽

Large B Cell

Abstract Casestudy A 52-year-old female presented with night sweats, chills, anorexia, and weight loss. Computed tomography and positron emission tomography showed a soft tissue infiltration in the anterior mediastinum and hypermetabolic bilateral supraclavicular, mediastinal, right hilar, and left internal mammary lymph nodes. An anterior mediastinal mass resection and thymectomy was subsequently performed. Results Sections of the mediastinal mass showed Hodgkin/Reed-Sternberg cells (HRS) admixed with small lymphocytes, histiocytes, plasma cells, and eosinophils. The HRS cells are positive for CD30, CD15, and MUM1, faintly positive for PAX5, and negative for CD20, CD45, CD79a, and BCL6. The morphology and immunophenotype is diagnostic of nodular sclerosis classic Hodgkin lymphoma (CHL). Sections of the thymectomy specimen showed similar morphology, however, in an area that represents 10-20% of the specimen, there are nodular and diffuse lymphoid infiltrates consisting of small lymphocytes, histiocytes, and large atypical cells. The large atypical cells are positive for CD20, CD23, CD30, CD45, CD79a, BCL2, BCL6, MUM-1, and PAX5, and negative for CD1a, CD3, CD57, and Cyclin D1. The background small CD3-positive lymphocytes form a rosette around most of the large atypical cells. CD21 and CD23 stains highlight residual follicular structures. In situ hybridization for EBV-encoded RNA (EBER) is negative. The presence of residual follicular meshwork with an immunophenotype of large B cell lymphoma supports a diagnosis of a gray zone lymphoma (GZL). Overall, CHL is involving 80-90% and GZL is involving 10-20% of the thymic tissue. The patient was subsequently placed on ABVD chemotherapy and achieved remission. Conclusion An accurate diagnosis of GZL is challenging. GZL is a rare type of lymphoma with morphological features between CHL and diffuse large B-cell lymphoma (DLBCL). It is even rarer to encounter a CHL concurrently present with a GZL. The optimal therapeutic approach for cases with concurrent lymphoma diagnosed with CHL and GZL needs further investigation.

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