Mohanty Sagarajit, Charles Cano Fiorella, Gabdoulline Razif, Lai Courteney K, Othman Basem, Sudarsanam Harish, Eder Thomas, Grebien Florian, Lipka Daniel B, Henschler Reinhard, Heuser Michael
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY.
Blood Adv. 2025 Aug 12;9(15):3887-3899. doi: 10.1182/bloodadvances.2024015739.
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.
核孔蛋白98（NUP98）::核受体结合SET结构域蛋白1（NSD1）是急性髓系白血病（AML）中最常见的核孔蛋白98（NUP98）融合之一。NUP98::NSD1阳性AML常与不良预后及对传统治疗反应不佳相关。然而，为确定新的潜在靶点以开发更好的治疗方法所做的研究有限。C型凝集素结构域家族12成员A（CLEC12A）是一种细胞表面受体，与健康造血干细胞相比，其在白血病干细胞中差异表达。我们发现NUP98::NSD1患者及用NUP98::NSD1融合致癌基因转化的小鼠AML细胞中均有CLEC12A的强烈过表达。为了解Clec12a在NUP98::NSD1 AML中的作用，我们使用CRISPR/Cas9方法在NUP98::NSD1 +NRASG12D永生化细胞中降低Clec12a的表达。与NUP98::NSD1 +NRASG12D/Clec12a野生型细胞相比，NUP98::NSD1 +NRASG12D/Clec12a基因敲除细胞在体外具有更高水平的凋亡和更低的集落数。重要的是，Clec12a的缺失显著降低了NUP98::NSD1 +NRASG12D小鼠模型的白血病植入并延长了生存期。我们的数据表明进一步探索CLEC12A作为治疗NUP98::NSD1 AML的潜在靶点。
