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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalLeukemia
DOIs
StateAccepted/In press - Mar 29 2018

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Interleukin-1 Receptor-Associated Kinases
Acute Myeloid Leukemia
Myeloid Cells
Therapeutics
Heterografts
Leukemia
Phosphotransferases
Site-Directed Mutagenesis
11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
Innate Immunity

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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; Kaempf, Andy; Elferich, Johannes; McDermott, Jason E.; Liu, Tao; Payne, Samuel H.; Shinde, Ujwal; Rodland, Karin D.; Mori, Motomi (Tomi); Druker, Brian; Singer, Jack W.; Agarwal, Anupriya.

In: Leukemia, 29.03.2018, p. 1-14.

Research output: Contribution to journalArticle

Hosseini, MM, Kurtz, SE, Abdelhamed, S, Mahmood, S, Davare, M, Kaempf, A, Elferich, J, McDermott, JE, Liu, T, Payne, SH, Shinde, U, Rodland, KD, Mori, MT, Druker, B, Singer, JW & Agarwal, A 2018, 'Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes', Leukemia, pp. 1-14. https://doi.org/10.1038/s41375-018-0112-2
Hosseini, Mona M. ; Kurtz, Stephen E. ; Abdelhamed, Sherif ; Mahmood, Shawn ; Davare, Monika ; Kaempf, Andy ; Elferich, Johannes ; McDermott, Jason E. ; Liu, Tao ; Payne, Samuel H. ; Shinde, Ujwal ; Rodland, Karin D. ; Mori, Motomi (Tomi) ; Druker, Brian ; Singer, Jack W. ; Agarwal, Anupriya. / Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. In: Leukemia. 2018 ; pp. 1-14.
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AU - Elferich, Johannes

AU - McDermott, Jason E.

AU - Liu, Tao

AU - Payne, Samuel H.

AU - Shinde, Ujwal

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AU - Druker, Brian

AU - Singer, Jack W.

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