Clec12a is required for the pathogenesis of NUP98::NSD1 AML
NUP98::NSD1 is one of the most recurring nucleoporin 98 (NUP98) fusions in acute myeloid leukemia (AML). NUP98::NSD1 positive AML is often associated with adverse outcomes and poor response to conventional treatments. However, limited studies have been done to identify new potential targets to develop better treatment approaches. The C-type lectin domain family 12 member A (CLEC12A) is a cell surface receptor that is differentially expressed in leukemic stem cells compared with healthy hematopoietic stem cells. We found a strong CLEC12A overexpression in both NUP98::NSD1 patients and murine AML cells transformed with the NUP98::NSD1 fusion oncogene. To understand the role of Clec12a in NUP98::NSD1 AML, we depleted Clec12a expression in NUP98::NSD1+NRASG12D-immortalized cells using the CRISPR/Cas9 approach. NUP98::NSD1+NRASG12D/Clec12a knockout cells had higher apoptosis levels and lower colony numbers in vitro compared with NUP98::NSD1+NRASG12D/Clec12a wild-type cells. Importantly, the deletion of Clec12a significantly reduced leukemic engraftment and prolonged survival of the NUP98::NSD1+NRASG12D murine model. Our data suggest to further explore CLEC12A as a potential target for the treatment of NUP98::NSD1 AML.
Authors
- Reinhard Henschler (ORCID: https://orcid.org/0000-0002-5895-4259)
- Sagarajit Mohanty (ORCID: https://orcid.org/0000-0001-7935-7798)
- Daniel B. Lipka (ORCID: https://orcid.org/0000-0001-5081-7869)
- Fiorella Charles Cano
- Thomas Eder (ORCID: https://orcid.org/0000-0002-0932-2052)
- Michael Heuser (ORCID: https://orcid.org/0000-0001-5318-9044)
- Cheng‐Kuo Lai (ORCID: https://orcid.org/0000-0001-8677-8013)
- Razif Gabdoulline (ORCID: https://orcid.org/0000-0002-4780-1134)
- Harish Sudarsanam
- Florian Grebien (ORCID: https://orcid.org/0000-0003-4289-2281)
- Basem Othman
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Veterinary Medicine Vienna (AT)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Medizinische Hochschule Hannover (DE)
- National Center for Tumor Diseases (DE)
- Cancer Research Institute of the Slovak Academy of Sciences (SK)
- St Anna Children's Hospital (AT)
- University Hospital Leipzig (DE)
- CeMM Research Center for Molecular Medicine (AT)
- Vienna Biocenter (AT)
- University Hospital in Halle (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Epigenomics (Germany) (DE)
- Leipzig University (DE)
Publication Details
- Journal
- Blood Advances
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1182/bloodadvances.2024015739
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Medizinischen Hochschule Hannover
- José Carreras Leukämie-Stiftung
- Deutsche Krebshilfe