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Acute myeloid leukemia

Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia

Leukemia volume 33, pages 1360–1372 (2019)Cite this article

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Abstract

Acute myeloid leukemia (AML) with co-occurring NUP98-NSD1 and FLT3-ITD is associated with unfavorable prognosis and represents a particularly challenging treatment group. To identify novel effective therapies for this AML subtype, we screened patient cells and engineered cell models with over 300 compounds. We found that mouse hematopoietic progenitors co-expressing NUP98-NSD1 and FLT3-ITD had significantly increased sensitivity to FLT3 and MEK-inhibitors compared to cells expressing either aberration alone (P < 0.001). The cells expressing NUP98-NSD1 alone had significantly increased sensitivity to BCL2-inhibitors (P = 0.029). Furthermore, NUP98-NSD1+/FLT3-ITD+ patient cells were also very sensitive to BCL2-inhibitor navitoclax, although the highest select sensitivity was found to SRC/ABL-inhibitor dasatinib (mean IC50 = 2.2 nM). Topoisomerase inhibitor mitoxantrone was the least effective drug against NUP98-NSD1+/FLT3-ITD+ AML cells. Of the 25 significant hits, four remained significant also compared to NUP98-NSD1-/FLT3-ITD+ AML patients. We found that SRC/ABL-inhibitor dasatinib is highly synergistic with BCL2-inhibitor navitoclax in NUP98-NSD1+/FLT3-ITD+ cells. Gene expression analysis supported the potential relevance of dasatinib and navitoclax by revealing significantly higher expression of BCL2A1, FGR, and LCK in NUP98-NSD1+/FLT3-ITD+ patients compared to healthy CD34+ cells. Our data suggest that dasatinib–navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3-ITD.

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Acknowledgements

We thank the patients and healthy donors who participated in this study. We would also like to thank staff at the FIMM High-Throughput Biomedicine Unit for their expert technical assistance with the drug screening experiments and the FIMM Sequencing Unit for their assistance with sequence analysis. We are grateful to laboratory technicians Alun Parsons, Minna Suvela, and Siv Knaappila for sample processing. We acknowledge personnel at the Biomedicum Helsinki FACS core and Functional Genomics Unit for their help with flow cytometry and RCV-tests. This work was supported by grants from Finnish Funding Agency for Technology and Innovation (grant number 40336/09). Personal grant support was received from the Väre Foundation for Pediatric Cancer Research, Ida Montin Foundation, the Cancer Society of Finland, and Finnish Hematology Association (JK). JS and AT were supported by grants from the Swiss Cancer League (KFS-3487-08-2014).

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Authors and Affiliations

  1. Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland

    Jarno L. Kivioja, Ashwini Kumar, Muntasir M. Majumder, Komal K. Javarappa, Samuli Eldfors & Caroline A. Heckman

  2. Department of Biomedicine, University Children’s Hospital, University of Basel, Basel, Switzerland

    Angeliki Thanasopoulou & Juerg Schwaller

  3. Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland

    Mika Kontro, Bhagwan Yadav & Kimmo Porkka

  4. Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

    Mika Kontro & Kimmo Porkka

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  1. Jarno L. Kivioja
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Correspondence to Caroline A. Heckman.

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KP has received honoraria and research funding from Celgene, Novartis, and Pfizer. CAH has received research funding from Celgene, Novartis, Orion, and Innovative Medicines Initiatives 2 project HARMONY. The remaining authors declare that they have no conflict of interest.

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Kivioja, J.L., Thanasopoulou, A., Kumar, A. et al. Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia. Leukemia 33, 1360–1372 (2019). https://doi.org/10.1038/s41375-018-0327-2

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