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Acute myeloid Leukemia

Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes

Leukemia volume 32, pages 2374–2387 (2018)Cite this article

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Abstract

Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden. Kinase profiling indicated pacritinib has potent inhibitory activity against IRAK1. Computational modeling combined with site-directed mutagenesis demonstrated high-affinity binding of pacritinib to the IRAK1 kinase domain. Pacritinib exposure reduced IRAK1 phosphorylation in AML cells. A higher percentage of primary AML samples showed robust sensitivity to pacritinib, which inhibits FLT3, JAK2, and IRAK1, relative to FLT3 inhibitor quizartinib or JAK1/2 inhibitor ruxolitinib, demonstrating the importance of IRAK1 inhibition. Pacritinib inhibited the growth of AML cells harboring a variety of genetic abnormalities not limited to FLT3 and JAK2. Pacritinib treatment reduced AML progenitors in vitro and the leukemia burden in AML xenograft model. Overall, IRAK1 contributes to the survival of leukemic cells, and the suppression of IRAK1 may be beneficial among heterogeneous AML subtypes.

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Acknowledgements

This study was supported by National Institutes of Health grant 5R00CA151670-03 (AA), V Foundation Scholar Award (AA), American Cancer Society Research Scholar Award (AA), CTI Biopharma (AA), NIH Build Exito Pilot project (AA) and 1U01CA214116-01 (Rodland/Druker). BJD is a Howard Hughes Medical Institute Investigator and is supported by the Leukemia & Lymphoma Society Beat AML initiative. MM is an NIH Build Exito scholar. The authors thank Peter Kurre, Cristina Tognon, and Pierrette Lo for their critical feedback; Brian Junio for compiling the clinical characteristics data for primary AML samples. Dorian LaTocha and Brianna Garcia for flow cytometry data acquisition and analysis; Marina A. Gritsenko, Therese R. Clauss, Matthew E. Monroe, and Ronald J. Moore for help with phosphoproteomics; and Sarah Bowden for administrative support.

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Authors and Affiliations

  1. Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Mona M. Hosseini, Stephen E. Kurtz, Shawn Mahmood, Brian J. Druker & Anupriya Agarwal

  2. Department of Pediatrics and Pediatric Blood &Cancer Biology Program, Oregon Health & Science University, Portland, OR, USA

    Sherif Abdelhamed & Monika A. Davare

  3. Biostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Andy Kaempf & Motomi Mori

  4. Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, USA

    Johannes Elferich & Ujwal Shinde

  5. Pacific Northwest National Laboratory, Richland, WA, USA

    Jason E. McDermott, Tao Liu, Samuel H. Payne & Karin D. Rodland

  6. Howard Hughes Medical Institute, Portland, OR, USA

    Brian J. Druker

  7. CTI BioPharma Corp, Seattle, WA, USA

    Jack W. Singer

  8. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA

    Anupriya Agarwal

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  1. Mona M. Hosseini
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Correspondence to Anupriya Agarwal.

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JWS is employed by and has equity ownership in CTI BioPharma, Corp. The authors report no other potential conflicts of interest to declare.

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Hosseini, M.M., Kurtz, S.E., Abdelhamed, S. et al. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia 32, 2374–2387 (2018). https://doi.org/10.1038/s41375-018-0112-2

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