Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)
| Autor: | Stephan Kreher, Lukas Kenner, Kathrin D Wurster, Olaf Merkel, Nikolai Schleussner, Arjan Diepstra, Reiner Siebert, Bernd Gillissen, Ioannis Anagnostopoulos, Mariantonia Costanza, Selina Glaser, Björn Lamprecht, Arturo Molina, Karl Köchert, Harald Stein, Korinna Jöhrens, Michael Hummel, Martin Janz, Stephan Mathas |
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| Přispěvatelé: | Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
C-Met CD74 TUMOR-CELLS Major histocompatibility complex SURFACE EXPRESSION ALK translocation Article T cell lymphoma T-Zell-Lymphom ACTIVATION PATHWAY invariant chain chemistry.chemical_compound immune system diseases hemic and lymphatic diseases PERIPHERAL T-CELL medicine Anaplastic lymphoma kinase T-cell lymphoma Cytotoxic T cell ddc:610 INVARIANT CHAIN CD74 MHC-II Anaplastic large-cell lymphoma Invariante Kette RC254-282 Crizotinib MIF Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Lymphoma Oncology chemistry Cancer research SURVIVAL C-MET HODGKIN DDC 610 / Medicine & health medicine.drug |
| Zdroj: | Cancers Volume 13 Issue 19 Cancers, 13(19):5012. MDPI AG Cancers, Vol 13, Iss 5012, p 5012 (2021) |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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