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

1
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
2
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
3
National Centre for Cell Science, Pune 411007, India
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Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
5
Precision NanoSystems Inc., Vancouver, BC V6P 6T7, Canada
6
AxolabsGmbH, 95326 Kulmbach, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 2766; https://doi.org/10.3390/cancers12102766
Received: 23 July 2020 / Revised: 20 September 2020 / Accepted: 21 September 2020 / Published: 26 September 2020
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.
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. View Full-Text
Keywords: AML; NUP98-NSD1; NRASG12D; siRNA; liposome AML; NUP98-NSD1; NRASG12D; siRNA; liposome
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MDPI and ACS Style

Mohanty, S.; Jyotsana, N.; Sharma, A.; Kloos, A.; Gabdoulline, R.; Othman, B.; Lai, C.K.; Schottmann, R.; Mandhania, M.; Schmoellerl, J.; Grebien, F.; Ramsay, E.; Thomas, A.; Vornlocher, H.-P.; Ganser, A.; Thol, F.; Heuser, M. Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia. Cancers 2020, 12, 2766. https://doi.org/10.3390/cancers12102766

AMA Style

Mohanty S, Jyotsana N, Sharma A, Kloos A, Gabdoulline R, Othman B, Lai CK, Schottmann R, Mandhania M, Schmoellerl J, Grebien F, Ramsay E, Thomas A, Vornlocher H-P, Ganser A, Thol F, Heuser M. Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia. Cancers. 2020; 12(10):2766. https://doi.org/10.3390/cancers12102766

Chicago/Turabian Style

Mohanty, Sagarajit, 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, and Michael Heuser. 2020. "Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia" Cancers 12, no. 10: 2766. https://doi.org/10.3390/cancers12102766

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