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HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment

Oncogene volume 36, pages 3441–3449 (2017)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells in the hematopoietic system and lymphoid tissues. Although inhibitors targeting the B-cell receptor (BCR) pathway have been successful in the treatment of the disease, the underlying mechanisms leading to BCR over-activity in CLL are not fully understood. In this study, we found that HSP90, a highly conserved molecular chaperone, is overexpressed in CLL compared with resting B cells. HSP90 overexpression is accompanied by the overexpression of several BCR kinases including LYN, spleen tyrosine kinase, Bruton tyrosine kinase and AKT. Chemical and immune-precipitation demonstrated that these BCR constituents are present in a multi-client chaperone complex with HSP90. Inhibition of HSP90 with PU-H71 destabilized the BCR kinases and caused apoptosis of CLL cells through the mitochondrial apoptotic pathway. Further, PU-H71 induced apoptosis in the presence of stromal co-culture or cytoprotective survival signals. Finally, genetic knockdown of HSP90 and its client AKT, but not BTK, reduced CLL viability. Overall, our study suggests that the chaperone function of HSP90 contributes to the over-activity of the BCR signaling in CLL and inhibition of HSP90 has the potential to achieve a multi-targeting effect. Thus, HSP90 inhibition may be explored to prevent or overcome drug resistance to single targeting agents.

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References

  1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS . Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107: 265–276.

    Article  CAS  PubMed  Google Scholar 

  2. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  PubMed  Google Scholar 

  3. Rai KR, Jain P . Chronic lymphocytic leukemia (CLL)-then and now. Am J Hematol 2016; 91: 330–340.

    Article  CAS  PubMed  Google Scholar 

  4. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  PubMed  Google Scholar 

  5. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007.

    Article  CAS  PubMed  Google Scholar 

  6. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: 88–94.

    Article  CAS  PubMed  Google Scholar 

  7. Sharman J, Hawkins M, Kolibaba K, Boxer M, Klein L, Wu M et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood 2015; 125: 2336–2343.

    Article  CAS  PubMed  Google Scholar 

  8. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152: 714–726.

    Article  CAS  PubMed  Google Scholar 

  9. Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J et al. Mutations driving CLL and their evolution in progression and relapse. Nature 2015; 526: 525–530.

    Article  CAS  PubMed  Google Scholar 

  10. Puente XS, Bea S, Valdes-Mas R, Villamor N, Gutierrez-Abril J, Martin-Subero JI et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 2015; 526: 519–524.

    Article  CAS  PubMed  Google Scholar 

  11. Shrestha L, Patel HJ, Chiosis G . Chemical tools to investigate mechanisms associated with HSP90 and HSP70 in disease. Cell Chem Biol 2016; 23: 158–172.

    Article  CAS  PubMed  Google Scholar 

  12. Scaltriti M, Dawood S, Cortes J . Molecular pathways: targeting hsp90–who benefits and who does not. Clin Cancer Res 2012; 18: 4508–4513.

    Article  CAS  PubMed  Google Scholar 

  13. Trentin L, Frasson M, Donella-Deana A, Frezzato F, Pagano MA, Tibaldi E et al. Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia. Blood 2008; 112: 4665–4674.

    Article  CAS  Google Scholar 

  14. Hertlein E, Wagner AJ, Jones J, Lin TS, Maddocks KJ, Towns WH 3rd et al. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood 2010; 116: 45–53.

    Article  CAS  PubMed  Google Scholar 

  15. Walsby E, Pearce L, Burnett AK, Fegan C, Pepper C . The Hsp90 inhibitor NVP-AUY922-AG inhibits NF-kappaB signaling, overcomes microenvironmental cytoprotection and is highly synergistic with fludarabine in primary CLL cells. Oncotarget 2012; 3: 525–534.

    Article  PubMed  Google Scholar 

  16. Gerecitano J, Modi S, Rampal R, Drilon AE, Fury MG, Gounder MM et al. Phase I trial of the HSP-90 inhibitor PU-H71. J Clin Oncol 2015; 33: abstr 2537.

    Article  Google Scholar 

  17. Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM et al. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol 2011; 7: 818–826.

    Article  CAS  PubMed  Google Scholar 

  18. Zong H, Gozman A, Caldas-Lopes E, Taldone T, Sturgill E, Brennan S et al. A hyperactive signalosome in acute myeloid leukemia drives addiction to a tumor-specific Hsp90 species. Cell Rep 2015; 13: 2159–2173.

    Article  CAS  PubMed  Google Scholar 

  19. Taldone T, Ochiana SO, Patel PD, Chiosis G . Selective targeting of the stress chaperome as a therapeutic strategy. Trends Pharmacol Sci 2014; 35: 592–603.

    Article  CAS  PubMed  Google Scholar 

  20. Goldstein RL, Yang SN, Taldone T, Chang B, Gerecitano J, Elenitoba-Johnson K et al. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J Clin Invest 2015; 125: 4559–4571.

    Article  PubMed  Google Scholar 

  21. Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ . Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 1996; 10: 456–459.

    CAS  PubMed  Google Scholar 

  22. Balakrishnan K, Burger JA, Wierda WG, Gandhi V . AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood 2009; 113: 149–153.

    Article  CAS  PubMed  Google Scholar 

  23. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91: 3379–3389.

    CAS  PubMed  Google Scholar 

  24. Grzybowska-Izydorczyk O, Cebula B, Robak T, Smolewski P . Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia. Eur J Cancer 2010; 46: 800–810.

    Article  CAS  PubMed  Google Scholar 

  25. Hayden RE, Pratt G, Roberts C, Drayson MT, Bunce CM . Treatment of chronic lymphocytic leukemia requires targeting of the protective lymph node environment with novel therapeutic approaches. Leuk Lymphoma 2012; 53: 537–549.

    Article  CAS  PubMed  Google Scholar 

  26. Burger JA . Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program 2011; 2011: 96–103.

    Article  Google Scholar 

  27. Andersen OS . Membrane proteins: through thick and thin. Nat Chem Biol 2013; 9: 667–668.

    Article  CAS  PubMed  Google Scholar 

  28. Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL . Functional characterization of BTK mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia 2015; 29: 895–900.

    Article  CAS  PubMed  Google Scholar 

  29. Guo A, Lu P, Galanina N, Nabhan C, Smith SM, Coleman M et al. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib. Oncotarget 2015; 7: 4598–4610.

    PubMed Central  Google Scholar 

  30. Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 2014; 28: 649–657.

    Article  CAS  PubMed  Google Scholar 

  31. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92.

    Article  CAS  PubMed  Google Scholar 

  32. Duhren-von Minden M, Ubelhart R, Schneider D, Wossning T, Bach MP, Buchner M et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 2012; 489: 309–312.

    Article  PubMed  Google Scholar 

  33. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 2014; 370: 2352–2354.

    Article  CAS  PubMed  Google Scholar 

  34. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014; 370: 2286–2294.

    Article  PubMed  Google Scholar 

  35. Liu TM, Woyach JA, Zhong Y, Lozanski A, Lozanski G, Dong S et al. Hypermorphic mutation of phospholipase C, gamma2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 2015; 126: 61–68.

    Article  CAS  PubMed  Google Scholar 

  36. Song Z, Lu P, Furman RR, Leonard JP, Martin P, Tyrell L et al. Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib. Clin Cancer Res 2010; 16: 587–599.

    Article  CAS  PubMed  Google Scholar 

  37. Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H et al. BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia. Ann Hematol. 2016; 95: 1979–1988.

    Article  CAS  PubMed  Google Scholar 

  38. Yang C, Lu P, Lee FY, Chadburn A, Barrientos JC, Leonard JP et al. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib. Leukemia 2008; 22: 1755–1766.

    Article  CAS  PubMed  Google Scholar 

  39. Lu P, Yang C, Guasparri I, Harrington W, Wang YL, Cesarman E . Early events of B-cell receptor signaling are not essential for the proliferation and viability of AIDS-related lymphoma. Leukemia 2009; 23: 807–810.

    Article  CAS  PubMed  Google Scholar 

  40. Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A et al. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget 2015; 6: 43881–43896.

    PubMed Central  PubMed  Google Scholar 

  41. Cheng S, Coffey G, Zhang XH, Shaknovich R, Song Z, Lu P et al. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood 2011; 118: 6342–6352.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago and,

    A Guo, P Lu, J Lee, C Zhen & Y L Wang

  2. USA and Department of Medicine, Program in Chemical Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    G Chiosis

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  1. A Guo
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  2. P Lu
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Correspondence to Y L Wang.

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Competing interests

Memorial Sloan-Kettering Cancer Center holds the intellectual rights to PU-H71 (GC). Samus Therapeutics, of which GC has partial ownership, has licensed PU-H71. The remaining authors declare no conflict of interest.

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Guo, A., Lu, P., Lee, J. et al. HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene 36, 3441–3449 (2017). https://doi.org/10.1038/onc.2016.494

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