Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia

• Main Authors: Sagarajit Mohanty, Nidhi Jyotsana, Amit Sharma, Arnold Kloos, Razif Gabdoulline, Basem Othman, Courteney K. Lai, Renate Schottmann, Madhvi Mandhania, Johannes Schmoellerl, Florian Grebien, Euan Ramsay, Anitha Thomas, Hans-Peter Vornlocher, Arnold Ganser, Felicitas Thol, Michael Heuser
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: Cancers
• Subjects: AML; NUP98-NSD1; NRASG12D; siRNA; liposome
• Online Access: https://www.mdpi.com/2072-6694/12/10/2766

NUP98-NSD1-positive acute myeloid leukemia (AML) is a poor prognostic subgroup that is frequently diagnosed in pediatric cytogenetically normal AML. NUP98-NSD1-positive AML often carries additional mutations in genes including <i>FLT3, NRAS, WT1,</i> and <i>MYC</i>. The purpose of our study was to characterize the cooperative potential of the fusion and its associated Neuroblastoma rat sarcoma (NRAS) mutation. By constitutively expressing NUP98-NSD1 and NRASG12D in a syngeneic mouse model and using a patient-derived xenograft (PDX) model from a NUP98-NSD1-positive AML patient, we evaluated the functional role of these genes and tested a novel siRNA formulation that inhibits the oncogenic driver NUP98-NSD1. NUP98-NSD1 transformed murine bone marrow (BM) cells in vitro and induced AML in vivo. While NRASG12D expression was insufficient to transform cells alone, co-expression of NUP98-NSD1 and NRASG12D enhanced the leukemogenicity of NUP98-NSD1. We developed a NUP98-NSD1-targeting siRNA/lipid nanoparticle formulation that significantly prolonged the survival of the PDX mice. Our study demonstrates that mutated NRAS cooperates with NUP98-NSD1 and shows that direct targeting of the fusion can be exploited as a novel treatment strategy in NUP98-NSD1-positive AML patients.