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Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL).

ABSTRACT: In 50-60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK⁺) ALCL. Key pathogenic events in ALK-negative (ALK^-) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK⁺ and ALK^- ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK⁺ ALCL or of CD95 death-receptor signaling in ALK^- ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.

SUBMITTER: Wurster KD

PROVIDER: S-EPMC8507667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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From Pathology to Precision Medicine in Anaplastic Large Cell Lymphoma Expressing Anaplastic Lymphoma Kinase (ALK+ ALCL).

Project description:Anaplastic large cell lymphoma expressing anaplastic lymphoma kinase (ALK+ ALCL) is a distinct subtype of non-Hodgkin lymphoma. In this review, we discuss the historical findings that led to its classification as a unique disease, despite its varied clinical presentation and histology. We discuss the molecular mechanisms underlying ALK+ ALCL pathology and the questions that remain in the field. Finally, we visit how decades of ALK+ ALCL research has yielded more precise drugs that hold promise for the future.

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The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL).

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Our Experience in Diagnosing and Treating Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL).

Project description:Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T-cell lymphoma detected in association with textured implants. It presents as a fluid accumulation around the implant, usually years after the implantation. We present our experience in diagnosing and treating four patients with BIA-ALCL, each widely differing from the other. Data on patients' surgical history, relevant medical information, and findings on pathological slides were retrieved from their medical charts and retrospectively reviewed. Each of the four patients was diagnosed with BIA-ALCL, one after breast augmentation, one after breast reconstruction with an implant, one after breast reconstruction with a latissimus dorsi flap and implant, and the fourth after the removal of breast implants. The cases were presented to a multidisciplinary team and subsequently underwent surgery. All four are currently free of tumors, as established by a negative follow-up via positron emission tomography-computed tomography. Although the incidence of BIA-ALCL is rare, these cases emphasize the need to rule out the diagnosis of BIA-ALCL in patients with textured implants or a history of implanted textured devices who present with symptoms such as late seroma or peri-implant mass. This pathology is typically indolent and slow-growing and heightened awareness for an early diagnosis could lead to quicker intervention and enhanced patient management.

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Expression signature characteristic of Anaplastic Large Cell Lymphoma (ALCL) patients

Project description:RNA extracted from tumor biopsies of 44 patients affected by ALCL was analyzed on the nCounter system using a custom panel called VF_150921 (Nanostring Technologies).

2023-12-06 | GSE217426 | GEO

ALK+ Anaplastic Large Cell Lymphoma (ALCL)-Derived Exosomes Carry ALK Signaling Proteins and Interact with Tumor Microenvironment

Project description:Simple Summary ALK+ anaplastic large cell lymphoma (ALK+ ALCL) is a distinct type of aggressive non-Hodgkin lymphoma of T-cell origin, which is characterized by overexpression and activation of ALK kinase due to chromosomal translocations of the gene. The most frequent chromosomal aberration is the t(2;5) resulting in the NPM-ALK chimeric protein, which exerts its oncogenic functions through activation of multiple oncogenic pathways. Exosomes, the best characterized type of extracellular vesicles, are secreted from the tumor cells, thus transferring signals to other cells that uptake exosomes. In this study, we demonstrate that ALK+ ALCL cells secrete exosomes that carry critical molecules of ALK signaling, which can be taken up by other cells with significant biologic effects including functional interactions with tumor microenvironment cells, which may contribute to tumor aggressiveness and possibly resistance to treatment. Abstract The oncogenic pathways activated by the NPM-ALK chimeric kinase of ALK+ anaplastic large cell lymphoma (ALCL) are well characterized; however, the potential interactions of ALK signaling with the microenvironment are not yet known. Here we report that ALK+ ALCL-derived exosomes contain critical components of ALK signaling as well as CD30, and that exosome uptake by lymphoid cells led to increased proliferation and expression of critical antiapoptotic proteins by the recipient cells. The bone marrow fibroblasts highly uptake ALK+ ALCL-derived exosomes and acquire a cancer-associated fibroblast (CAF) phenotype. Moreover, exosome-mediated activation of stromal cells altered the cytokine profile of the microenvironment. These interactions may contribute to tumor aggressiveness and possibly resistance to treatment.

| S-EPMC9221431 | biostudies-literature

Identification of C/EBP? target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.

Project description:C/EBP? (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBP? responsible for ALK-mediated oncogenesis. C/EBP? was knocked down in ALK+ ALCL cell lines with a C/EBP?-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBP?. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBP? was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBP?-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBP? in ALK-mediated oncogenesis.

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BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL.

Project description:Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

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Transcription profiling of 32 human Anaplastic Large Cell Lymphomas (ALCL) and 5 ALCL cell lines to investigate differences between tumors expressing/not-expressing Anaplastic Lymphoma kinkase

Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Affymetrix UU133A gene expression data for a series of 32 cases of systemic Anaplastic Large Cell Lymphoma (ALCL) and 5 ALCL cell lines; used to (1) confirm that tumors expressing Anaplastic Lymphoma Kinase (ALK+ ALCL) and ALK- ALCLs are different entities, (2) identify most significantly differentially expressed genes between ALK+ and ALK- samples, (3) generate a molecular signature of ALK- ALCL, (4) perform unsupervised analysis classifying ALCL in sub-groups related to morphology and clinical variables (e.g. disease stage and enrichment with 'early relapse' patients). Principal Investigator: Dr Georges DELSOL-- Centre de Physiopathologie Toulouse-Purpan CHU-Purpan -- Toulouse -- France -- Email: delsol.g@chu-toulouse.fr Programme "Cartes d'identite des Tumeurs" (CIT) of the "Ligue Nationale Contre le Cancer" (LNCC) Submitter: Fabien PETEL (petelf@ligue-cancer.net)

2007-05-05 | E-TABM-117 | biostudies-arrayexpress

Synchronous breast implant associated anaplastic large cell lymphoma (BIA-ALCL) and silicone induced granuloma of breast implant capsule (SIGBIC): What to learn.

Project description:We recently described silicone induced granuloma of breast implant capsule (SIGBIC) as an implant capsule illness related to intact silicone breast implants. The precursor to SIGBIC development is gel bleeding/shedding from the implant shell/interior content. Currently, although the literature widely discussed the pathogenesis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), the trigger point for its development is still a black-box. In this case report, we report a 46-year-old woman with SIGBIC diagnosis in her right breast and BIA-ALCL in her left breast, diagnosed with ultrasound and breast magnetic resonance. Microscopy confirmed silicone bleeding from the implant surface/ content. The imaging findings reported that SIGBIC and BIA-ALCL were similar; however, BIA-ALCL had an intracapsular collection.

| S-EPMC7396908 | biostudies-literature

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