Cancers, Vol. 12, Pages 2766: Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia

Cancers, Vol. 12, Pages 2766: Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia Cancers doi: 10.3390/cancers12102766 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 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 FLT3, NRAS, WT1, and MYC. 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...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research