Data from Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma
Shuyun RaoKathy Q. CaiJason StadanlickNoa Greenberg‐KushnirNehal Solanki-PatelSang-Yun LeeShawn P. FahlJoseph R. TestaDavid L. Wiest
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<div>Abstract<p>Mutations in ribosomal proteins cause bone marrow failure syndromes associated with increased cancer risk, but the basis by which they do so remains unclear. We reported previously that the ribosomal protein Rpl22 is a tumor suppressor in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), and that loss of just one <i>Rpl22</i> allele accelerates T-cell lymphomagenesis by activating NF-κB and inducing the stem cell factor Lin28B. Here, we show that, paradoxically, loss of both alleles of <i>Rpl22</i> restricts lymphoma progression through a distinct effect on migration of malignant cells out of the thymus. Lymphoma-prone AKT2-transgenic or PTEN-deficient mice on an <i>Rpl22<sup>−/−</sup></i> background developed significantly larger and markedly more vascularized thymic tumors than those observed in <i>Rpl22<sup>+/+</sup></i> control mice. But, unlike <i>Rpl22<sup>+/+</sup></i> or <i>Rpl22<sup>+/−</sup></i> tumors, <i>Rpl22<sup>−/−</sup></i> lymphomas did not disseminate to the periphery and were retained in the thymus. We traced the defect in <i>the Rpl22</i><sup>−/−</sup> lymphoma migratory capacity to downregulation of the KLF2 transcription factor and its targets, including the key migratory factor sphingosine 1-phosphate receptor 1 (S1PR1). Indeed, reexpression of S1PR1 in Rpl22-deficient tumor cells restores their migratory capacity <i>in vitro</i>. The regulation of KLF2 and S1PR1 by Rpl22 appears to be proximal as Rpl22 reexpression in Rpl22-deficient lymphoma cells restores expression of KLF2 and S1P1R, while Rpl22 knockdown in Rpl22-sufficient lymphomas attenuates their expression. Collectively, these data reveal that, while loss of one copy of <i>Rpl22</i> promotes lymphomagenesis and disseminated disease, loss of both copies impairs responsiveness to migratory cues and restricts malignant cells to the thymus. <i>Cancer Res; 76(11); 3387–96. ©2016 AACR</i>.</p></div>AbstractA cellular phosphoprotein that binds to and inactivates p53 has recently been identified as a product of the oncogene MDM2. Amplification of the MDM2 gene was found in more than a third of sarcomas and in a subset of malignant gliomas. Despite the absence of amplification, the MDM2 gene was overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non-Hodgkin's lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL) and B-NHL. This suggests that MDM2 could play a role, via the p53 pathway, in tumorigenicity and/or in disease progression in some hematological malignancies. However, in the light of our findings that, in a few cases, both the overexpression of MDM2 and mutant-type p53 was seen, it is possible that MDM2 overexpression may also promote neoplastic growth by mechanisms other than inactivation of the p53 protein.Key Words: MDM2p53B-CLLlow-grade lymphoma
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Inappropriate activation of c-mesenchymal-epithelial transition (MET), the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and represented a promising therapeutic target for developing anticancer agents. In contrast to other solid tumors, there are limited data describing the functional role of HGF/c-MET signaling pathway in lymphoma. In the current review, we summarize recent findings about the expression, cellular mechanisms/functions, and therapeutic application of HGF/c-MET in different types of lymphoma, especially B cell lymphoma, T and NK cell lymphoma, and Hodgkin lymphoma. We also discuss the existing problems and future directions about studying the HGF/c-MET pathway in lymphoma cells.
Hematology
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Burkitt's lymphoma
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Hui-Jen Tsaiabcd, Neng-Yao Shiha, Sung-Hsin Kuoe, Ann-Lii Chenge, Hui-You Lina, Tsai-Yun Chenb, Kung-Chao Changf, Sheng-Fung Linc, Jeffrey S. Changa & Li-Tzong Chenabgh*a National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwanb Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwanc Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwand Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwane Department of Oncology, National Taiwan University Hospital, Taipei, Taiwanf Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwang Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwanh Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan
Hematology
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Burkitt's lymphoma
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Epstein-Barr Virus (EBV) is associated with several B-cell non-Hodgkin's lymphoma (NHL), but the role of EBV in diffuse large B-cell lymphoma (DLBCL) is poorly defined. Several studies indicated the expression of phosphorylated STAT3 (pSTAT3) is predominant in EBV(+)- DLBCL, of which its activated form can promote the downstream oncogenes expression such as c-MYC. c-MYC gene rearrangements are frequently found in aggressive lymphoma with inferior prognosis. Furthermore, EBV is a co-factor of MYC dysregulation. JAK1/STAT3 could be the downstream pathway of EBV and deregulates MYC. To confirm the involvement of EBV in JAK1/ STAT3 activation and MYC deregulation, association of EBV, pSTAT3 and MYC in EBV(+)- DLBCL cases were studied. The presence of pSTAT3 and its upstream proteins: pJAK1 is identify to delineate the role of EBV in JAK1/STAT3 pathway.51 cases of DLBCL paraffin-embedded tissue samples were retrieved from a single private hospital in Kuala Lumpur, Malaysia. EBER-ISH was performed to identify the EBV expression; ten EBV(+)-DLBCL cases subjected to immunohistochemistry for LMP1, pJAK1, pSTAT3 and MYC; FISH assay for c-MYC gene rearrangement.Among 10 cases of EBV(+)-DLBCL, 90% were non-GCB subtype (p=0.011), 88.9% expressed LMP1. 40% EBV(+)-DLBCL had pJAK1 expression.66.7% EBV(+)-DLBCL showed the positivity of pSTAT3, which implies the involvement of EBV in constitutive JAK/STAT pathway. 44.5% EBV(+)-DLBCL have co-expression of pSTAT3 and MYC, but all EBV(+)-DLBCL was absence with c-MYC gene rearrangement. The finding of clinical samples might shed lights to the lymphomagenesis of EBV associated with non-GCB subtypes, and the potential therapy for pSTAT3-mediated pathway.
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c-Myc (hereafter referred to as Myc) protein plays a fundamental role in cell cycle regulation, proliferation, differentiation, and apoptosis by modulating the expression of a large number of targets [1]. Expression of Myc is frequently deregulated in human cancers and is often associated with aggressive disease. In non-Hodgkin lymphomas, although Myc has been described as a defining feature and the driving oncogene for Burkitt lymphoma, Myc overexpression has also been recognized in other aggressive B-cell lymphomas and has been linked to adverse prognosis [2]. In addition to Burkitt lymphoma, these aggressive lymphomas include Myc-associated diffuse large B-cell lymphoma (DLBCL), double-hit lymphoma, acute lymphoblastic lymphoma, a blastic variant of mantle cell lymphoma (MCL), transformed follicular lymphoma, and plasmablastic lymphoma. However, mechanisms underlying the sustained activation of Myc and subsequent contribution to clinical fatality are unclear. Recently, Myc transcriptional network has been shown to also include microRNAs [3]. These small non-protein-coding, single-stranded RNAs function as negative regulators of mRNA and affect virtually every aspect of tumorigenesis [3]. Although Myc can alter a large set of miRNAs, rather than activation, the majority of identified miRNAs are repressed by Myc [4]. Among these repressed miRNAs, many are putative tumor suppressors, such as let-7, miR-15a/16-1, miR-26a, miR-29, and miR-34a. Each of these miRNAs has been associated with anti-proliferative, pro-apoptotic, and/or anti-tumorigenic activity. Reactivating these miRNAs in Myc-transformed B lymphoma cell lines dramatically inhibits tumorigenesis [4], indicating that reconstituting lymphoma with these tumor suppressor miRNAs could be therapeutically beneficial in Myc-associated lymphomas. Therefore, it is likely that Myc hyperactivity contributes to widespread repression of miRNA expression and that Myc-driven miRNA repression underlies the molecular mechanisms related to lymphoma aggressive transformation.
We recently explored the role of epigenetic regulation in Myc-mediated miRNA repression [5]. We revealed 1) loss or low expression of c-Myc-regulated miRNAs in aggressive B-cell lymphomas; 2) reverse correlation of tumor suppressor miRNAs such as miR-26a and miR29-a-c with Myc as well as cell proliferation, CDK6, and IGF-1R expression; 3) ectopic expression of miR-26a, miR-29 suppression of CDK-6, and IGF-1R and Myc-driven cell proliferation in aggressive lymphoma cell lines and primary lymphomas; and 4) miR-26a and miR-29 repression as a result of Myc/HDAC3 and EZH2 (a catalytic component of polycomb repressive complex 2, PRC2) interaction. Results of these studies have led to the identification of a novel model for interplay between Myc, HDAC3, PRC2, and miRNAs and their contribution to Myc-associated lymphomagenesis, and HDAC3/EZH2/miRNAs as novel therapeutic targets. Myc, HDCA3, and PRC2 form a repressive complex tethered to miR-29a/b1 and miR-29b2/c promoter regulatory elements to epigenetically repress transcription of these miRNAs in Myc-expressing lymphoma cells and that subsequent miR-29 down-regulation results in induction of oncogenic proteins (CDK6 and IGF-1R) and Myc-driven lymphomagenesis. Furthermore, we demonstrated that Myc contributes to the upregulation of EZH2 via repressing EZH2-targeting miR-26a and that EZH2 in turn induces Myc expression via Myc-targeting miR-494, thereby generating a positive feedback loop to ensure persistent high protein levels of Myc and EZH2 and further repression of miR-29, which could be involved in maintaining sustained Myc activation and malignant phenotype. More importantly, these findings provided therapeutic rational and opportunities for treating aggressive B-cell lymphomas by attacking Myc through epigenetically modulating Myc upstream “targeting-Myc miRNAs” such as miR-494 as well as attacking Myc downstream “Myc-targeting miRNAs” such as miR-29 through histone modification (Figure (Figure1).1). Indeed, our study showed that treatment with the pan-HDAC inhibitor SAHA, the EZH2 inhibitor DZNep, and their specific siRNAs disrupted Myc hyperactivity, resulting in enhanced restoration of miR-29a-c expression, down-regulation of miR-29 targeting genes CDK6 and IGF-1R, and suppression of lymphoma cell growth ex vivo and in vivo. In line with our findings, it was recently shown that the EZH2 inhibitor GSK126 effectively inhibited the proliferation of EZH2-mutant DLBCL cell lines and markedly inhibited the growth of EZH2-mutant DLBCL mouse xenografts, supporting EZH2 inhibition as a therapeutic strategy for lymphoma therapy [6].
Figure 1
Epigenetically targeting c-Myc and c-Myc-regulated genes for aggressive B-cell lymphoma therapy
Different approaches have been taken to find ways to therapeutically target Myc in cancer, and however, efforts to target Myc activity have proven unsuccessful. Until recently, Bradner and colleagues found a way to inhibit Myc indirectly [7]. They devised JQ1, a small molecule that prevents bromodomain from binding to acetylated histone, silencing c-Myc transcription. JQ1 functions as a specific inhibitor of bromodomain-containing protein 4 through an interference of acetyl-lysine recognition domains (bromodomains). When applied to Myc harboring multiple myeloma and Burkitt lymphoma, they showed that treatment with JQ1 leads to a profound cell-cycle arrest and apoptosis of the cell lines with associated reduction in Myc transcription and protein expression ex vivo and in murine models of multiple myeloma [7]. Moreover, Mertz and colleagues extended these findings to reveal a survival benefit in murine xenograft models of Burkitt lymphoma [8]. However, silencing Myc with JQ1 for combinatorial therapy of aggressive B-cell lymphomas has not been reported. A study by us strongly supported the further development and testing of a combination of JQ1 with EZH2 and/or HDAC3 inhibitor against aggressive B-cell lymphomas [5].
Most recently, seminal studies have demonstrated that PI3K is indispensable for lymphoma survival and that it cooperates with c-Myc in Burkitt lymphomagenesis [9-10]. These important findings support that B-cell receptor (BCR)-PI3K axis and c-Myc pathway act in concert to contribute to lymphoma treatment resistance and aggressive progression. With newly established BCR signaling inhibitors, it is inspiring to exploit synthetically lethal targeting of BCR-PI3K axis (using PCI-32765, CAL101), and Myc pathway (JQ-1, DZNep) for these lymphomas. Functional identification of Myc activation mechanisms and its interplay with other survival pathways such as BCR will allow us to gain insight into lymphoma survival and progression and provide novel biological targets for aggressive lymphomas.
Follicular lymphoma
Aggressive lymphoma
BCL10
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Various types of tumor suppressor genes (TSG) have been reported to be mutated in malignant lymphoma. Point mutation and deletion are the major mechanisms that inactivate TSG. Alterations of the p53 gene have been analyzed well in lymphoid malignancies, and point mutations have been proved to have an important role in the progression or aggressiveness of B cell lymphoma. Recently, the silencing of gene expression by DNA hypermethylation was proposed as an alternative mechanism in inactivation of TSG. The p73, p15INK4B, and p16INK4A genes are targets of such epigenetic alterations. The ATM, PTEN, and SNF5/INI1 genes are also reported to be mutated in T and/or B cell malignancies. Recurrent chromosomal deletion may indicate the loss of candidate TSGs in the deleted interval. Cytogenetic and molecular analyses have revealed frequent and recurrent hemizygous chromosomal deletions at 6p, 6q, and 13p in malignant lymphoma. These deleted intervals have been intensively investigated to identify the candidate TSG that imply the pathogenesis of malignant lymphoma. As mentioned above, many TSG are mutated in malignant lymphoma, and these alterations could be critical in the development and progression of lymphoma. Comprehensive study of TSG is essential to understand the biological characteristics of malignant lymphoma.
BCL10
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Abstract Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1–targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit.
Venetoclax
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The B-cell lymphoma 6 transcriptional repressor is the most commonly involved oncogene in B-cell lymphomas. Sustained expression of B-cell lymphoma 6 causes malignant transformation of germinal center B cells. Understanding the mechanism of action of B-cell lymphoma 6 is crucial for the study of how aberrant transcriptional programming leads to lymphomagenesis and development of targeted antilymphoma therapy.Identification of B-cell lymphoma 6 target genes indicates a critical role for B-cell lymphoma 6 in facilitating a state of physiological genomic instability required for germinal center B cells to undergo affinity maturation, and suggests its contribution to several additional cellular functions. The discovery of several layers of counterregulatory mechanisms reveals how B cells can control and fine-tune the potentially lymphomagenic actions of B-cell lymphoma 6. From the biochemical standpoint, B-cell lymphoma 6 can regulate distinct biological pathways through different cofactors. This observation explains how the biological actions of B-cell lymphoma 6 can be physiologically controlled through separate mechanisms and affords the means for improved therapeutic targeting. The fact that patients with B-cell lymphoma 6-dependent lymphoma can be identified on the basis of gene signatures suggests that therapeutic trials of B-cell lymphoma 6 inhibitors could be personalized to these individuals.B-cell lymphoma 6 plays a fundamental role in lymphomagenesis and is an excellent therapeutic target for development of improved antilymphoma therapeutic regimens.
Pathogenesis
B-cell lymphoma
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