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

Hosseini, Mona M.; Kurtz, Stephen E.; Abdelhamed, Sherif; Mahmood, Shawn; Davare, Monika A.; Kaempf, Andy; Elferich, Johannes; McDermott, Jason E.; Liu, Tao; Payne, Samuel H.; Shinde, Ujwal; Rodland, Karin D.; Mori, Motomi; Druker, Brian; Singer, Jack W.; Agarwal, Anupriya

doi:10.1038/s41375-018-0112-2

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

Journal Article · Thu Mar 29 00:00:00 EDT 2018 · Leukemia

DOI:https://doi.org/10.1038/s41375-018-0112-2· OSTI ID:1507759

Hosseini, Mona M. ^[1]; Kurtz, Stephen E. ^[1]; Abdelhamed, Sherif ^[1]; Mahmood, Shawn ^[1]; Davare, Monika A. ^[1]; Kaempf, Andy ^[1]; Elferich, Johannes ^[1];

^[2];

^[2]; Shinde, Ujwal ^[1];

^[2]; Mori, Motomi ^[1]; Druker, Brian ^[3]; Singer, Jack W. ^[4]; Agarwal, Anupriya ^[1]

Oregon Health & Science Univ., Portland, OR (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Oregon Health & Science Univ., Portland, OR (United States); Howard Hughes Medical Inst., Portland, OR (United States)
CTI BioPharma Corporation, Seattle, WA (United States)

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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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1507759

Report Number(s):: PNNL-SA-137772

Journal Information:: Leukemia, Vol. 32, Issue 11; ISSN 0887-6924

Publisher:: Nature Publishing Group (NPG)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 34 works

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