This article highlights the presentations from the 2021 scientific meeting of the Club Hematopoiesis and Oncogenesis. This annual meeting focuses on hematopoiesis and oncogenic mechanisms. Various ...topics were presented: expansion of hematopoietic stem cells with in vivo and ex vivo strategies, the role of the hematopoietic stem cell niches in aging and leukemic resistance, the crossroad between hematology and immunology, the importance of the metabolism in normal hematopoiesis and hematopoietic defects, solid tumors and oncogenesis, the noncoding genome, inflammation in monocyte differentiation and leukemia, and importantly, the recent advances in myeloid malignancies, lymphoid leukemia and lymphoma.
Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK+ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional ...transgenic models of anaplastic lymphoma kinase–positive (ALK+) lymphomas and human ALK+ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK+ cells, and demonstrate extracellular HMGB-1–stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-κB pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK+ cells, which express the IL-8 receptors CXCR1 and CXCR2. In vitro and in vivo, HMGB-1 inhibition achieved by glycyrrhizin treatment led to a drastic reduction in ALK+ cell invasiveness. The pathophysiological relevance of our observations was confirmed by demonstrating that the HMGB-1 and IL-8 receptors are expressed in ALK+ALCL biopsies. We have also shown that IL-8 secretion is correlated with leukemic dissemination of ALK+ cells in a significant number of patients. The results of the present study demonstrate for the first time a relationship among the pro-inflammatory mediators HMGB-1, MMP-9, PAR-2, and IL-8. We propose that these mediators create a premetastatic niche within the skin, thereby participating in ALK+ lymphoma epidermotropism.
AUF1/heterogeneous nuclear ribonucleoprotein D (hnRNPD) binds to adenylate uridylate-rich elements contained in the 3' untranslated region of many short-lived mRNAs. This binding has been shown in ...vitro to control the stability of adenylate uridylate-rich element-containing mRNAs, including mRNAs encoding proto-oncogenes, cytokines, or other signaling molecules. However, no studies have yet been undertaken to identify the mRNAs subject to AUF1-mediated regulation in vivo. The purpose of our study was to investigate the biological functions of AUF1. Thus, we derived transgenic (Tg) mice, which overexpress one isoform of AUF1, the p37(AUF1). Mice of the three Tg lines analyzed exhibit altered levels of expression of several target mRNAs, such as c-myc, c-jun, c-fos, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor alpha. The Tg line with the highest amount of Tg p37(AUF1) protein developed sarcomas. The tumors strongly expressed AUF1 Tg protein and Cyclin D1. Taken together, our data show that: (a) AUF1 is a key regulatory factor of gene expression in vivo; and (b) the deregulation of this heterogeneous nuclear ribonucleoprotein leads to tumorigenesis.
NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) and TPM3-ALK (nonmuscular tropomyosin 3-anaplastic lymphoma kinase) are oncogenic tyrosine kinases implicated in the pathogenesis of human ...ALK-positive lymphoma. We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EμSRα enhancer/promoter. The expression of either oncogene resulted in the arrest of the differentiation of early B cells and lymphomagenesis. We also observed the development of skin keratoacanthoma lesions, probably because of aberrant ALK expression in keratinocytes. The inactivation of the ALK oncogene on doxycycline treatment was sufficient to induce sustained regression of both hematopoietic tumors and skin disease. Importantly, treatment with the specific ALK inhibitor (PF-2341066) also reversed the pathologic states, showing the value of these mouse models for the validation of ALK tyrosine kinase inhibitors. Thus, our results show (1) that NPM-ALK and TPM3-ALK oncogenes are sufficient for lymphoma/leukemia development and required for tumor maintenance, hence validating ALK as potentially effective therapeutic target; and (2) for the first time, in vivo, the equal tumorigenic potential of the NPM-ALK and TPM3-ALK oncogenic tyrosine kinases. Our models offer a new tool to investigate in vivo the molecular mechanisms associated with ALK-induced lymphoproliferative disorders.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it ...activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM-ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM-ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.
In Epstein-Barr virus-associated Hodgkin's lymphomas, neoplastic Reed-Sternberg cells and surrounding non-tumor B-cells contain different variants of the LMP1-BNLF1 oncogene. In this study, we raised ...the question of functional properties of latent membrane protein 1 (LMP1) natural variants from both Reed-Sternberg and non-tumor B-cells.
Twelve LMP1 natural variants from Reed-Sternberg cells, non-tumor B-cells of Hodgkin's lymphomas and from B-cells of benign reactive lymph nodes were cloned, sequenced and stably transfected in murine recombinant interleukin-3-dependent Ba/F3 cells to search for relationships between LMP1 cellular origin and oncogenic properties as well as nuclear factor-kappaB activation, and apoptosis protection.
LMP1 variants of Reed-Sternberg cell origin were often associated with increased mutation rate and with recurrent genetic events, such as del15bp associated with S to N replacement at codon 309, and four substitutions I85L, F106Y, I122L, and M129I. Oncogenic potential (growth factor-independence plus clonogenicity) was consistently associated with LMP1 variants from Reed-Sternberg cells, but inconstantly for LMP1-variants from non-tumor B-cells. Analysis of LMP1 variants from both normal B-cells and Reed-Sternberg cells indicates that protection against apoptosis through activation of nuclear factor-kappaB - whatever the cellular origin of LMP1 - was maintained intact, regardless of the mutational pattern.
Taken together, our results demonstrate that preserved nuclear factor-kappaB activity and protection against apoptosis would be the minimal prerequisites for all LMP1 natural variants from both normal and tumor cells in Hodgkin's lymphomas, and that oncogenic potential would constitute an additional feature for LMP1 natural variants in Reed-Sternberg cells.
This report describes two cases of human herpesvirus-8 (HHV-8)–associated large cell lymphoma of the bowel in human immunodeficiency virus (HIV)–positive men. Immunohistochemistry provides evidence ...of HHV-8 infection of the lymphoma cells (LNA1+, vIL-6+). In both cases, lymphoma cells were coinfected by the Epstein-Barr virus. One case was of B-cell lineage, but the second one was of null phenotype with isolated expression of the CD3 molecule. However, in the latter case, assessment of B- or T-cell clonality remained elusive. The chief finding for these two cases was the lack of history of primary effusion lymphoma. There was an apparent restriction of the tumor to the large bowel in the first case. For the second case, the bowel tumor was preceded by lymph node and liver involvement. The cases suggest that the incidence of HHV-8 infection in large cell lymphoma arising in the setting of HIV infection (other than primary effusion lymphoma) may be underestimated and that the detection of the viral gene products would be appropriate for greater understanding of the pathogenesis of these tumors. HUM PATHOL 33:846-849. Copyright 2002, Elsevier Science (USA). All rights reserved.
The repair DNA polymerase beta (Polbeta), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of ...Polbeta has been reported in many tumor types that exhibit genetic aberrations, including EBV-related B-cell lymphomas. However, the mechanisms responsible for its overexpression have never been examined. Here, we report that both expression and activity of Polbeta, in EBV-immortalized B cells, are induced by several natural genetic variants of LMP1, an oncoprotein associated with the vast majority of EBV-related tumors. Conversely, we found that the expression of Polbeta decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-kappaB in the LMP1-mediated Polbeta regulation. Using electrophoretic mobility shift assay experiments from several EBV-immortalized B-cell nuclear extracts, we identified an LMP1-dependent p50/c-Rel heterodimer on a proximal kappaB binding site (-211 to -199nt) of the Polbeta promoter. This result was correlated with a specific Polbeta kappaB transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polbeta overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-kappaB activation.
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