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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)

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Item Type:Article
Title:Aberrant expression of and cell death induction by engagement of the MHC-II chaperone CD74 in anaplastic large cell lymphoma (ALCL)
Creators Name:Wurster, K.D. and Costanza, M. and Kreher, S. and Glaser, S. and Lamprecht, B. and Schleussner, N. and Anagnostopoulos, I. and Hummel, M. and Jöhrens, K. and Stein, H. and Molina, A. and Diepstra, A. and Gillissen, B. and Köchert, K. and Siebert, R. and Merkel, O. and Kenner, L. and Janz, M. and Mathas, S.
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.
Keywords:CD74, Invariant Chain, MHC-II, T Cell Lymphoma, ALK Translocation
Page Range:5012
Date:1 October 2021
Official Publication:https://doi.org/10.3390/cancers13195012
PubMed:View item in PubMed

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