Kreutmair, Stefanie 
ORCID: 0000-0001-8466-6675, Lippert, Lena Johanna, Klingeberg, Cathrin, Albers-Leischner, Corinna, Yacob, Salome, Shlyakhto, Valeria, Mueller, Tony, Mueller-Rudorf, Alina, Yu, Chuanjiang, Gorantla, Sivahari Prasad, Miething, Cornelius, Duyster, Justus and Illert, Anna Lena
(2022).
NIPA (Nuclear Interaction Partner of ALK) Is Crucial for Effective NPM-ALK Mediated Lymphomagenesis.
Front. Oncol., 12.
LAUSANNE:
FRONTIERS MEDIA SA.
ISSN 2234-943X
Abstract
The NPM-ALK fusion kinase is expressed in 60% of systemic anaplastic large-cell lymphomas (ALCL). A Nuclear Interaction Partner of ALK (NIPA) was identified as a binding partner of NPM-ALK. To identify the precise role of NIPA for NPM-ALK-driven lymphomagenesis, we investigated various NPM-ALK(+) cell lines and mouse models. Nipa deletion in primary mouse embryonic fibroblasts resulted in reduced transformation ability and colony formation upon NPM-ALK expression. Downregulating NIPA in murine NPM-ALK(+) Ba/F3 and human ALCL cells decreased their proliferation ability and demonstrated synergistic effects of ALK inhibition and NIPA knockdown. Comprehensive in vivo analyses using short- and long-latency transplantation mouse models with NPM-ALK(+) bone marrow (BM) revealed that Nipa deletion inhibited NPM-ALK-induced tumorigenesis with prolonged survival and reduced spleen colonies. To avoid off-target effects, we combined Nipa deletion and NPM-ALK expression exclusively in T cells using a lineage-restricted murine ALCL-like model resembling human disease: control mice died from neoplastic T-cell infiltration, whereas mice transplanted with Lck-Cre(TG/wt)Nipa(flox/flox) NPM-ALK(+) BM showed significantly prolonged survival. Immunophenotypic analyses indicated a characteristic ALCL-like phenotype in all recipients but revealed fewer stem-cell-like features of Nipa-deficient lymphomas compared to controls. Our results identify NIPA as a crucial player in effective NPM-ALK-driven ALCL-like disease in clinically relevant murine and cell-based models.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Creators: |
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| URN: | urn:nbn:de:hbz:38-690578 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.3389/fonc.2022.875117 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Front. Oncol. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume: | 12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date: | 2022 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | FRONTIERS MEDIA SA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | LAUSANNE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 2234-943X | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Language: | English | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncontrolled Keywords: |
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| URI: | http://kups.ub.uni-koeln.de/id/eprint/69057 |
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