https://phaidra.vetmeduni.ac.at/o:4524 Clec12a is required for the pathogenesis of NUP98::NSD1 AML Mohanty, Sagarajit Sagarajit Mohanty Charles Cano, Fiorella Fiorella Charles Cano Gabdoulline, Razif Razif Gabdoulline Lai, Courteney K. Courteney K. Lai Othman, Basem Basem Othman Sudarsanam, Harish Harish Sudarsanam Eder, Thomas Thomas Eder 0000-0002-0932-2052 University of Veterinary Medicine Vienna Grebien, Florian Florian Grebien 0000-0003-4289-2281 University of Veterinary Medicine Vienna Lipka, Daniel B. Daniel B. Lipka Henschler, Reinhard Reinhard Henschler Heuser, Michael Michael Heuser American Society of Hematology journal article open access eng NUP98::NSD1 is one of the most recurring nucleoporin 98 (NUP98) fusions in acute myeloid leukemia (AML). NSD1-driven AML is 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 (LSCs) compared to healthy hematopoietic stem cells (HSCs). We demonstrated a strong overexpression of CLEC12A in both NUP98::NSD1 patients and murine AML cells transformed with NUP98::NSD1. 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 showed higher levels of apoptosis and lower colony numbers in vitro compared to NUP98::NSD1+NRASG12D/Clec12a wildtype 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. Myeloid Neoplasia http://creativecommons.org/licenses/by-nc-nd/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4524/download 10.1182/bloodadvances.2024015739 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Blood Advances issn:2473-9529 VoR Blood Advances 9 15 2.31 MB 2025