Mohanty , S and Jyotsana , N and Sharma , A and Kloos , A and Gabdoulline, R and Othman, N and Lai , CK and Schottmann , R and Mandhania , M (2020) Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia. Cancers . 2020 Sep 26;12(10):2766, 12 (10). p. 2766.

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Abstract

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 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.

Item Type:	Article
Subjects:	Insect Molecular Biology
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	25 Apr 2021 08:21
Last Modified:	29 Nov 2021 11:18
URI:	http://nccs.sciencecentral.in/id/eprint/930

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