ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1454-1463 ◽  
Author(s):  
Nathalie Chevallier ◽  
Connie M. Corcoran ◽  
Christine Lennon ◽  
Elizabeth Hyjek ◽  
Amy Chadburn ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cell Lymphoma ◽  
Common Factor ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Dependent Manner ◽  
B Cell Lymphomas ◽  
Acute Leukemias

Abstract The multiplicity of transcription factors involved in hematologic malignancies suggests a complicated scenario in which many different molecular mechanisms lead to malignant transformation. We hypothesized that some of these proteins might physically and functionally interact and thus mechanistically link different diseases. The ETO protein of t(8;21) acute myeloid leukemia (AML) is an excellent candidate as a common factor because it is normally expressed in human hematopoietic cells, it binds to histone deacetylases (HDACs), and it interacts with the PLZF protein of t(11;17) acute promyelocytic leukemia. To determine whether ETO functionally links a broader range of disease entities, we asked whether ETO forms a complex with the Bcl-6 oncoprotein of B-cell lymphomas. We found that ETO and Bcl-6 are coexpressed in normal and malignant lymphoid tissue, where they interact and colocalize in nuclear speckles. ETO binds to the fourth zinc finger of Bcl-6, enhances Bcl-6 repression of artificial and endogenous genes in an HDAC-dependent manner, and forms a complex with Bcl-6 on the promoters of its endogenous target genes in B-cell lymphoma cells. Therefore, ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies.

scholarly journals Carnosol induces apoptotic cell death through ROS-dependent inactivation of STAT3 in human melanoma G361 cells

2019 ◽  
Vol 62 (1) ◽  
Author(s):  
Seung Mi Choi ◽  
Do-Hee Kim ◽  
Kyung-Soo Chun ◽  
Joon-Seok Choi
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Human Melanoma ◽  
Dependent Manner ◽  
Bax Protein ◽  
Wide Range ◽  
Anti Cancer ◽  
Induced Apoptosis

Abstract Melanoma is the leading cause of skin cancer deaths, and the poor prognosis of metastatic melanoma has made needs for a novel pharmacological treatment or efficient intervention. Carnosol, a major polyphenolic compound from Rosmarinus officinalis, has a wide range of biological activities including anti-cancer effect. However, the underlying molecular mechanisms of its anti-cancer effect remain poorly understood in malignant human melanoma cells. In the present study, we investigate the apoptotic effect and the underlying anti-cancer mechanisms of carnosol. Our results revealed that carnosol strongly induced apoptosis against human melanoma G361 cells in a dose- and time-dependent manner, and caused dramatical elevation in cellular reactive oxygen species (ROS) level during apoptosis. In mechanistic studies, carnosol treatment decreased protein level of anti-apoptotic B‑cell lymphoma 2 (Bcl-2) and B cell lymphoma-extra large (Bcl-xL), however, increased level of pro-apoptotic Bcl-2-associated X protein (Bax) protein. Moreover, carnosol escalated cellular level of p53, which was accompanied by a decline of mouse double minute 2 homolog (MDM2) level. Also, carnosol inhibited activation of Src and signal transducer and activator of transcription 3 (STAT3), therefore down-regulated STAT3-dependent gene expression, such as D-series cyclin and survivin. These changes by carnosol were attenuated by pre-treatment of N-acetyl cysteine, and abolished progression of carnosol-induced apoptosis. In conclusion, carnosol induced apoptosis in human melanoma G361 cells through ROS generation and inhibition of STAT3-mediated pathway. Our results provide molecular bases of carnosol-induced apoptosis, and suggest a novel candidate for human melanoma treatment.

scholarly journals Mir-155 Enhances B-Cell Lymphoma Growth By Targeting TBRG1

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4820-4820 ◽  
Author(s):  
Joost Kluiver ◽  
Izabella Slezak-Prochazka ◽  
Melanie Winkle ◽  
Lydia Visser ◽  
Arjan Diepstra ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Ectopic Expression ◽  
B Cell Lymphoma ◽  
Argonaute 2 ◽  
Rna Immunoprecipitation

Abstract Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B-cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, TBRG1 (NIAM1), TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the miR-155 target gene TBRG1 increased proliferation of BL cells. In primary B-cell lymphoma TBRG1-positive cases have significant lower levels of miR-155 as compared to TBRG1-negative cases, suggesting that TBRG1 is also regulated by miR-155 in primary B-cell lymphoma. Thus, our data indicate that miR-155 plays an oncogenic role in B-cell lymphoma by targeting the tumor suppressor TBRG1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice

Blood ◽  
2021 ◽  
Author(s):  
Miguel A Galindo-Campos ◽  
Nura Lutfi ◽  
Sarah Bonnin ◽  
Carlos Martínez ◽  
Talia Velasco-Hernandez ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cells ◽  
B Cell ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Tumour Progression ◽  
Cancer Therapeutics ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Parp 1

Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its overexpression has been linked with aggressive tumour progression. Here, we show that Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphomas. PARP-1 and PARP-2 catalyse the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA-strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphomas, while PARP-1-deficiency accelerates lymphomagenesis in the Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in pre-leukemic Em-Myc B cells resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1-deficiency induces a proinflammatory response, and an increase in regulatory T cells likely contributing to immune escape of B-cell lymphomas, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centred therapeutic strategies with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumours.

‘Piperazining’ the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib

2019 ◽  
Vol 11 (18) ◽  
pp. 2365-2380
Author(s):  
Aimen K Aljoundi ◽  
Clement Agoni ◽  
Fisayo A Olotu ◽  
Mahmoud ES Soliman
Keyword(s):  
Molecular Dynamics ◽  
B Cell ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dynamics Simulation ◽  
Large B Cell Lymphoma ◽  
Dynamics Simulations ◽  
Large B Cell

Aim: Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive. Materials & methods: This study therefore employed molecular dynamics simulations coupled with advanced post-molecular dynamics simulation techniques to unravel the structural mechanisms that inform the reported multitargeting ability of masitinib. Results: Molecular dynamics simulations revealed initial selective targeting of catalytic residues (Asp334/Glu335 – LYN; Asp130/Asp148/Glu54 – FYN; Asp89 – BLK) by masitinib, with high-affinity interactions via its piperazine ring at the entrance of the ATP-binding pockets, before systematic access into the hydrophobic deep pocket grooves. Conclusion: Identification of these ‘gatekeeper’ residues could open up a novel paradigm of structure-based design of highly selective pan-inhibitors of BCR signaling in the treatment of diffuse large B-cell lymphoma.

T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients.

1995 ◽  
Vol 13 (7) ◽  
pp. 1742-1750 ◽  
Author(s):  
J P Greer ◽  
W R Macon ◽  
R E Lamar ◽  
S N Wolff ◽  
R S Stein ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Combination Chemotherapy ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
B Cell Lymphomas ◽  
Intermediate Grade ◽  
Large B Cell

PURPOSE Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.

scholarly journals Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2121-2127 ◽  
Author(s):  
Hai-Jun Zhou ◽  
Lan V. Pham ◽  
Archito T. Tamayo ◽  
Yen-Chiu Lin-Lee ◽  
Lingchen Fu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Promoter Activation ◽  
Growth And Survival ◽  
Survival Mechanisms ◽  
Lymphoma Therapy ◽  
Receptor Family

Abstract CD40 is an integral plasma membrane–associated member of the TNF receptor family that has recently been shown to also reside in the nucleus of both normal B cells and large B-cell lymphoma (LBCL) cells. However, the physiological function of CD40 in the B-cell nucleus has not been examined. In this study, we demonstrate that nuclear CD40 interacts with the NF-κB protein c-Rel, but not p65, in LBCL cells. Nuclear CD40 forms complexes with c-Rel on the promoters of NF-κB target genes, CD154, BLyS/BAFF, and Bfl-1/A1, in various LBCL cell lines. Wild-type CD40, but not NLS-mutated CD40, further enhances c-Rel–mediated Blys promoter activation as well as proliferation in LBCL cells. Studies in normal B cells and LBCL patient cells further support a nuclear transcriptional function for CD40 and c-Rel. Cooperation between nuclear CD40 and c-Rel appears to be important in regulating cell growth and survival genes involved in lymphoma cell proliferation and survival mechanisms. Modulating the nuclear function of CD40 and c-Rel could reveal new mechanisms in LBCL pathophysiology and provide potential new targets for lymphoma therapy.

Abstract B38: FOXP1 truncated isoforms differentially regulate target genes in diffuse large B cell lymphoma.

2013 ◽  
Author(s):  
Emily Camilleri ◽  
Carlos Aya-Bonilla ◽  
Jamie Nourse ◽  
Philip J. Brown ◽  
Alison H. Banham ◽  
...  
Keyword(s):  
B Cell ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Truncated Isoforms ◽  
Large B Cell
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