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

Autor: Euan Ramsay, Arnold Kloos, Felicitas Thol, Anitha Thomas, Florian Grebien, Nidhi Jyotsana, Amit Sharma, Hans-Peter Vornlocher, Sagarajit Mohanty, Johannes Schmoellerl, Michael Heuser, Madhvi Mandhania, Basem Othman, Courteney K. Lai, Arnold Ganser, Razif Gabdoulline, Renate Schottmann
Rok vydání: 2020
Předmět:
Zdroj: Cancers
Volume 12
Issue 10
Cancers, Vol 12, Iss 2766, p 2766 (2020)
ISSN: 2072-6694
DOI: 10.3390/cancers12102766
Popis: Simple Summary NUP98-NSD1-positive acute myeloid leukemia (AML) frequently shows an additional mutation in Neuroblastoma rat sarcoma (NRAS). However, the synergistic effect of NUP98-NSD1 and NRASG12D in leukemic transformation remained unclear. In addition, NUP98-NSD1 positive AML patients respond poorly to chemotherapy and lack a targeted therapeutic option. Our study aimed to identify the cooperation of NUP98-NSD1 fusion and NRASG12D mutation and to develop a novel therapeutic approach for this AML. We found that NUP98-NSD1 alone can cause leukemia with long latency, and NRASG12D contributes to the aggressiveness of this AML. Additionally, we validated a novel NUP98-NSD1-targeting siRNA/lipid nanoparticle formulation that significantly prolonged the survival of patient-derived xenograft (PDX) mice with NUP98-NSD1-positive AML. 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.
Databáze: OpenAIRE
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