Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)
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 pr...
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| Veröffentlicht in: | Cancers 2021-10, Vol.13 (19), p.5012 |
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| creator | Wurster, Kathrin Costanza, Mariantonia Kreher, Stephan Glaser, Selina Lamprecht, Björn Schleussner, Nikolai Anagnostopoulos, Ioannis Hummel, Michael Jöhrens, Korinna Stein, Harald Molina, Arturo Diepstra, Arjan Gillissen, Bernd Köchert, Karl Siebert, Reiner Merkel, Olaf Kenner, Lukas Janz, Martin Mathas, Stephan |
| description | 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. |
| doi_str_mv | 10.3390/cancers13195012 |
| format | Article |
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13195012</identifier><identifier>PMID: 34638496</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Anaplastic large-cell lymphoma ; Antigen presentation ; Apoptosis ; Breakpoints ; c-Met protein ; CD95 antigen ; Cell death ; Cytotoxicity ; DNA methylation ; Flow cytometry ; Gene expression ; Invariant chain ; Kinases ; Leukemia ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Lymphoid cells ; Lymphoma ; Major histocompatibility complex ; Malignancy ; Medical prognosis ; Microscopy ; Monoclonal antibodies ; Peptides ; Phosphatase ; Protein-tyrosine kinase ; Proteins</subject><ispartof>Cancers, 2021-10, Vol.13 (19), p.5012</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-b98b7e6ed5f464320f034ca4736db00ad962f641d7a1276b9e9b6a70aeef5e53</citedby><cites>FETCH-LOGICAL-c398t-b98b7e6ed5f464320f034ca4736db00ad962f641d7a1276b9e9b6a70aeef5e53</cites><orcidid>0000-0002-5548-2022 ; 0000-0001-9239-1050 ; 0000-0003-2184-1338</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507667/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507667/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids></links><search><creatorcontrib>Wurster, Kathrin</creatorcontrib><creatorcontrib>Costanza, Mariantonia</creatorcontrib><creatorcontrib>Kreher, Stephan</creatorcontrib><creatorcontrib>Glaser, Selina</creatorcontrib><creatorcontrib>Lamprecht, Björn</creatorcontrib><creatorcontrib>Schleussner, Nikolai</creatorcontrib><creatorcontrib>Anagnostopoulos, Ioannis</creatorcontrib><creatorcontrib>Hummel, Michael</creatorcontrib><creatorcontrib>Jöhrens, Korinna</creatorcontrib><creatorcontrib>Stein, Harald</creatorcontrib><creatorcontrib>Molina, Arturo</creatorcontrib><creatorcontrib>Diepstra, Arjan</creatorcontrib><creatorcontrib>Gillissen, Bernd</creatorcontrib><creatorcontrib>Köchert, Karl</creatorcontrib><creatorcontrib>Siebert, Reiner</creatorcontrib><creatorcontrib>Merkel, Olaf</creatorcontrib><creatorcontrib>Kenner, Lukas</creatorcontrib><creatorcontrib>Janz, Martin</creatorcontrib><creatorcontrib>Mathas, Stephan</creatorcontrib><title>Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)</title><title>Cancers</title><description>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. 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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.</description><subject>Anaplastic large-cell lymphoma</subject><subject>Antigen presentation</subject><subject>Apoptosis</subject><subject>Breakpoints</subject><subject>c-Met protein</subject><subject>CD95 antigen</subject><subject>Cell death</subject><subject>Cytotoxicity</subject><subject>DNA methylation</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Invariant chain</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Lymphoid cells</subject><subject>Lymphoma</subject><subject>Major histocompatibility complex</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Microscopy</subject><subject>Monoclonal 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Stephan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)</atitle><jtitle>Cancers</jtitle><date>2021-10-07</date><risdate>2021</risdate><volume>13</volume><issue>19</issue><spage>5012</spage><pages>5012-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34638496</pmid><doi>10.3390/cancers13195012</doi><orcidid>https://orcid.org/0000-0002-5548-2022</orcidid><orcidid>https://orcid.org/0000-0001-9239-1050</orcidid><orcidid>https://orcid.org/0000-0003-2184-1338</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Anaplastic large-cell lymphoma Antigen presentation Apoptosis Breakpoints c-Met protein CD95 antigen Cell death Cytotoxicity DNA methylation Flow cytometry Gene expression Invariant chain Kinases Leukemia Lymphocytes Lymphocytes B Lymphocytes T Lymphoid cells Lymphoma Major histocompatibility complex Malignancy Medical prognosis Microscopy Monoclonal antibodies Peptides Phosphatase Protein-tyrosine kinase Proteins |
| title | 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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