Acute myeloid Leukemia

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

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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References

  1. 1.

    Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. Cancer. 2013;119:2720–7.

    Article  Google Scholar 

  2. 2.

    Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Eng J Med. 2013;368:2059–74.

    Article  Google Scholar 

  3. 3.

    Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.

    CAS  Article  Google Scholar 

  4. 4.

    Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(Pt 8):1281–3.

    CAS  Article  Google Scholar 

  5. 5.

    Traer E, Martinez J, Javidi-Sharifi N, Agarwal A, Dunlap J, English I, et al. FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. Cancer Res. 2016;76:6471–82.

    CAS  Article  Google Scholar 

  6. 6.

    Giles FJ, Krawczyk J, O’Dwyer M, Swords R, Freeman C. The role of inflammation in leukaemia. Adv Exp Med Biol. 2014;816:335–60.

    Article  Google Scholar 

  7. 7.

    Carey A, Edwards D, Eide CA, Newell L, Traer E, Medeiros B, et al. Identification of interleukin-1 by functional screening as a key mediator of cellular expansion and disease progression in acute myeloid leukemia. Cell Rep. 2017;18:p3204–18.

    Article  Google Scholar 

  8. 8.

    Zhang B, Chu S, Agarwal P, Campbell VL, Hopcroft L, Jorgensen HG, et al. Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells. Blood. 2016;128:2671–82.

    CAS  Article  Google Scholar 

  9. 9.

    Welner RS, Amabile G, Bararia D, Czibere A, Yang H, Zhang H, et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell. 2015;27:671–81.

    CAS  Article  Google Scholar 

  10. 10.

    Estrov Z, Kurzrock R, Estey E, Wetzler M, Ferrajoli A, Harris D, et al. Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors. Blood. 1992;79:1938–45.

    CAS  PubMed  Google Scholar 

  11. 11.

    Vanderwerf SM, Svahn J, Olson S, Rathbun RK, Harrington C, Yates J, et al. TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells. Blood. 2009;114:5290–8.

    CAS  Article  Google Scholar 

  12. 12.

    Jain A, Kaczanowska S, Davila E. IL-1 receptor-associated kinase signaling and its role in inflammation, cancer progression, and therapy resistance. Front Immunol. 2014;5:553.

    Article  Google Scholar 

  13. 13.

    Li Z, Younger K, Gartenhaus R, Joseph AM, Hu F, Baer MR, et al. Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. J Clin Invest. 2015;125:1081–97.

    Article  Google Scholar 

  14. 14.

    Dussiau C, Trinquand A, Lhermitte L, Latiri M, Simonin M, Cieslak A, et al. Targeting IRAK1 in T-cell acute lymphoblastic leukemia. Oncotarget. 2015;6:18956–65.

    Article  Google Scholar 

  15. 15.

    Rhyasen GW, Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, et al. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell. 2013;24:90–104.

    CAS  Article  Google Scholar 

  16. 16.

    Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature. 2010;465:885–90.

    CAS  Article  Google Scholar 

  17. 17.

    Jimenez C, Sebastian E, Chillon MC, Giraldo P, Mariano Hernandez J, Escalante F, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenstrom’s macroglobulinemia. Leukemia. 2013;27:1722–8.

    CAS  Article  Google Scholar 

  18. 18.

    Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia. Blood. 2013;122:1222–32.

    CAS  Article  Google Scholar 

  19. 19.

    Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.

    CAS  Article  Google Scholar 

  20. 20.

    Yang D, Chen W, Xiong J, Sherrod CJ, Henry DH, Dittmer DP. Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma. Proc Natl Acad Sci USA. 2014;111:E4762–8.

    CAS  Article  Google Scholar 

  21. 21.

    Wee ZN, Yatim SM, Kohlbauer VK, Feng M, Goh JY, Bao Y, et al. IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel. Nat Commun. 2015;6:8746.

    CAS  Article  Google Scholar 

  22. 22.

    Adams AK, Bolanos LC, Dexheimer PJ, Karns RA, Aronow BJ, Komurov K, et al. IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. Oncotarget. 2015;6:43395–407.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ye ZH, Gao L, Wen DY, He Y, Pang YY, Chen G. Diagnostic and prognostic roles of IRAK1 in hepatocellular carcinoma tissues: an analysis of immunohistochemistry and RNA-sequencing data from the cancer genome atlas. Onco Targets Ther. 2017;10:1711–23.

    CAS  Article  Google Scholar 

  24. 24.

    Rhyasen GW, Starczynowski DT. IRAK signalling in cancer. Br J Cancer. 2015;112:232–7.

    CAS  Article  Google Scholar 

  25. 25.

    Rhyasen GW, Bolanos L, Starczynowski DT. Differential IRAK signaling in hematologic malignancies. Exp Hematol. 2013;41:1005–7.

    CAS  Article  Google Scholar 

  26. 26.

    Beverly LJ, Starczynowski DT. IRAK1: oncotarget in MDS and AML. Oncotarget. 2014;5:1699–1700.

    Article  Google Scholar 

  27. 27.

    Liang K, Volk AG, Haug JS, Marshall SA, Woodfin AR, Bartom ET, et al. Therapeutic targeting of MLL degradation pathways in MLL-rearranged leukemia. Cell. 2017;168:59–72 e13.

    CAS  Article  Google Scholar 

  28. 28.

    Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011;29:1039–45.

    CAS  Article  Google Scholar 

  29. 29.

    Poulsen A, William A, Blanchard S, Lee A, Nagaraj H, Wang H, et al. Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3). J Comput Aided Mol Des. 2012;26:437–50.

    CAS  Article  Google Scholar 

  30. 30.

    Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, et al. Results of the persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts 100,000/µl late breaking abstract at 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego; 2016.

  31. 31.

    Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4:e225–36.

    Article  Google Scholar 

  32. 32.

    Agarwal A, Mackenzie RJ, Besson A, Jeng S, Carey A, LaTocha DH, et al. BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. Blood. 2014;124:3260–73.

    CAS  Article  Google Scholar 

  33. 33.

    Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med. 2005;201:915–23.

    CAS  Article  Google Scholar 

  34. 34.

    Desterke C, Bilhou-Nabera C, Guerton B, Martinaud C, Tonetti C, Clay D, et al. FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis. Cancer Res. 2011;71:2901–15.

    CAS  Article  Google Scholar 

  35. 35.

    Choudhary C, Brandts C, Schwable J, Tickenbrock L, Sargin B, Ueker A, et al. Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood. 2007;110:370–4.

    CAS  Article  Google Scholar 

  36. 36.

    Komrokji RS, Seymour JF, Roberts AW, Wadleigh M, To LB, Scherber R, et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood. 2015;125:2649–55.

    CAS  Article  Google Scholar 

  37. 37.

    Singer JW, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R, Verstovsek S. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol. 2016;8:11–9.

    CAS  Article  Google Scholar 

  38. 38.

    Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43:D512–20.

    CAS  Article  Google Scholar 

  39. 39.

    Schwartz D, Gygi SP. An iterative statistical approach to the identification of protein phosphorylation motifs from large-scale data sets. Nat Biotechnol. 2005;23:1391–8.

    CAS  Article  Google Scholar 

  40. 40.

    Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF, et al. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood. 2012;120:1290–8.

    CAS  Article  Google Scholar 

  41. 41.

    Starczynowski DT, Kuchenbauer F, Wegrzyn J, Rouhi A, Petriv O, Hansen CL, et al. MicroRNA-146a disrupts hematopoietic differentiation and survival. Exp Hematol. 2011;39:167–78. e164

    CAS  Article  Google Scholar 

  42. 42.

    Kristinsson SY, Bjorkholm M, Hultcrantz M, Derolf AR, Landgren O, Goldin LR. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J Clin Oncol. 2011;29:2897–903.

    Article  Google Scholar 

  43. 43.

    Lee KL, Ambler CM, Anderson DR, Boscoe BP, Bree AG, Brodfuehrer JI, et al. Discovery of clinical candidate 1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J Med Chem. 2017; 60: 5521–42.

  44. 44.

    William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6). 1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011;54:4638–58.

    CAS  Article  Google Scholar 

  45. 45.

    Hart S, Goh KC, Novotny-Diermayr V, Tan YC, Madan B, Amalini C, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J. 2011;1:e44.

    CAS  Article  Google Scholar 

  46. 46.

    Hart S, Goh KC, Novotny-Diermayr V, Hu CY, Hentze H, Tan YC, et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia. 2011;25:1751–9.

    CAS  Article  Google Scholar 

  47. 47.

    Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31:3681–7.

    CAS  Article  Google Scholar 

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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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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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