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Mediators of Inflammation
Volume 2015, Article ID 970242, 8 pages
http://dx.doi.org/10.1155/2015/970242
Review Article

HSP90 and HSP70: Implication in Inflammation Processes and Therapeutic Approaches for Myeloproliferative Neoplasms

1INSERM, UMR 866, Equipe Labellisée Ligue contre le Cancer and Association pour la Recherche contre le Cancer, La Ligue Nationale contre le Cancer, Laboratoire d’Excellence LipSTIC, 21000 Dijon, France
2Faculty of Medicine and Pharmacy, University of Burgundy, 21000 Dijon, France
3Service d’Hématologie Biologique, Pôle Biologie, 21000 Dijon, France
4Centre Anticancéreux Georges-François Leclerc, CGFL, 21000 Dijon, France

Received 30 July 2015; Accepted 27 September 2015

Academic Editor: Hans Carl Hasselbalch

Copyright © 2015 Margaux Sevin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. J. Baxter, L. M. Scott, P. J. Campbell et al., “Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders,” The Lancet, vol. 365, no. 9464, pp. 1054–1061, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. C. James, V. Ugo, J.-P. Le Couédic et al., “A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera,” Nature, vol. 434, no. 7037, pp. 1144–1148, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. R. Kralovics and R. C. Skoda, “Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders,” Blood Reviews, vol. 19, no. 1, pp. 1–13, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. R. L. Levine, M. Wadleigh, J. Cools et al., “Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis,” Cancer Cell, vol. 7, no. 4, pp. 387–397, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. T. L. Lasho, A. Pardanani, and A. Tefferi, “LNK mutations in JAK2 mutation-negative erythrocytosis,” The New England Journal of Medicine, vol. 363, no. 12, pp. 1189–1190, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. F. Delhommeau, S. Dupont, V. Della Valle et al., “Mutation in TET2 in myeloid cancers,” The New England Journal of Medicine, vol. 360, no. 22, pp. 2289–2301, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. F. Stegelmann, L. Bullinger, R. F. Schlenk et al., “DNMT3A mutations in myeloproliferative neoplasms,” Leukemia, vol. 25, no. 7, pp. 1217–1219, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. F. Ritossa, “A new puffing pattern induced by temperature shock and DNP in Drosophila,” Experientia, vol. 18, no. 12, pp. 571–573, 1962. View at Publisher · View at Google Scholar · View at Scopus
  9. M. J. Schlesinger, “Heat shock proteins,” The Journal of Biological Chemistry, vol. 265, no. 21, pp. 12111–12114, 1990. View at Google Scholar · View at Scopus
  10. S. Jindal, “Heat shock proteins: applications in health and disease,” Trends in Biotechnology, vol. 14, no. 1, pp. 17–20, 1996. View at Publisher · View at Google Scholar · View at Scopus
  11. C. Garrido, S. Gurbuxani, L. Ravagnan, and G. Kroemer, “Heat shock proteins: endogenous modulators of apoptotic cell death,” Biochemical and Biophysical Research Communications, vol. 286, no. 3, pp. 433–442, 2001. View at Publisher · View at Google Scholar · View at Scopus
  12. D. Lanneau, M. Brunet, E. Frisan, E. Solary, M. Fontenay, and C. Garrido, “Heat shock proteins: essential proteins for apoptosis regulation,” Journal of Cellular and Molecular Medicine, vol. 12, no. 3, pp. 743–761, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Didelot, D. Lanneau, M. Brunet et al., “Interaction of heat-shock protein 90β isoform (HSP90β) with cellular inhibitor of apoptosis 1 (c-IAP1) is required for cell differentiation,” Cell Death and Differentiation, vol. 15, no. 5, pp. 859–866, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. G. Jego, D. Lanneau, A. De Thonel et al., “Dual regulation of SPI1/PU.1 transcription factor by heat shock factor 1 (HSF1) during macrophage differentiation of monocytes,” Leukemia, vol. 28, no. 8, pp. 1676–1686, 2014. View at Publisher · View at Google Scholar · View at Scopus
  15. S. E. Craven, D. French, W. Ye, F. De Sauvage, and A. Rosenthal, “Loss of Hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndrome,” Blood, vol. 105, no. 9, pp. 3528–3534, 2005. View at Publisher · View at Google Scholar · View at Scopus
  16. J.-A. Ribeil, Y. Zermati, J. Vandekerckhove et al., “Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1,” Nature, vol. 445, no. 7123, pp. 102–105, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. A. de Thonel, J. Vandekerckhove, D. Lanneau et al., “HSP27 controls GATA-1 protein level during erythroid cell differentiation,” Blood, vol. 116, no. 1, pp. 85–96, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. W. B. Pratt and D. O. Toft, “Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery,” Experimental Biology and Medicine, vol. 228, no. 2, pp. 111–133, 2003. View at Google Scholar · View at Scopus
  19. L. Whitesell and S. L. Lindquist, “HSP90 and the chaperoning of cancer,” Nature Reviews Cancer, vol. 5, no. 10, pp. 761–772, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. P.-L. Hsu and S.-M. Hsu, “Abundance of heat shock proteins (hsp89, hsp60, and hsp27) in malignant cells of Hodgkin's disease,” Cancer Research, vol. 58, no. 23, pp. 5507–5513, 1998. View at Google Scholar · View at Scopus
  21. P. George, P. Bali, P. Cohen et al., “Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3,” Cancer Research, vol. 64, no. 10, pp. 3645–3652, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. L. Shang and T. B. Tomasi, “The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons,” The Journal of Biological Chemistry, vol. 281, no. 4, pp. 1876–1884, 2006. View at Publisher · View at Google Scholar · View at Scopus
  23. L. Whitesell, E. G. Mimnaugh, B. De Costa, C. E. Myers, and L. M. Neckers, “Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 18, pp. 8324–8328, 1994. View at Publisher · View at Google Scholar · View at Scopus
  24. J. Lewis, A. Devin, A. Miller et al., “Disruption of Hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-κB activation,” The Journal of Biological Chemistry, vol. 275, no. 14, pp. 10519–10526, 2000. View at Publisher · View at Google Scholar
  25. A.-L. Joly, G. Wettstein, G. Mignot, F. Ghiringhelli, and C. Garrido, “Dual role of heat shock proteins as regulators of apoptosis and innate immunity,” Journal of Innate Immunity, vol. 2, no. 3, pp. 238–247, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. E. M. Creagh, R. J. Carmody, and T. G. Cotter, “Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells,” Experimental Cell Research, vol. 257, no. 1, pp. 58–66, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. E. Schmitt, A. Parcellier, S. Gurbuxani et al., “Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant,” Cancer Research, vol. 63, no. 23, pp. 8233–8240, 2003. View at Google Scholar · View at Scopus
  28. L. M. Vargas-Roig, F. E. Gago, O. Tello, J. C. Aznar, and D. R. Ciocca, “Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy,” International Journal of Cancer, vol. 79, no. 5, pp. 468–475, 1998. View at Google Scholar · View at Scopus
  29. A. Brondani Da Rocha, A. Regner, I. Grivicich et al., “Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines,” International Journal of Oncology, vol. 25, no. 3, pp. 777–785, 2004. View at Google Scholar · View at Scopus
  30. S. Ray, Y. Lu, S. H. Kaufmann et al., “Genomic mechanisms of p210BCR-ABL signaling: induction of heat shock protein 70 through the GATA response element confers resistance to paclitaxel-induced apoptosis,” Journal of Biological Chemistry, vol. 279, no. 34, pp. 35604–35615, 2004. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Gallardo, S. Barrio, M. Fernandez et al., “Proteomic analysis reveals heat shock protein 70 has a key role in polycythemia Vera,” Molecular Cancer, vol. 12, article 142, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. F. Guo, C. Sigua, P. Bali et al., “Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells,” Apoptosis, vol. 105, no. 3, pp. 1246–1255, 2005. View at Google Scholar
  33. G. Jego, A. Hazoumé, R. Seigneuric, and C. Garrido, “Targeting heat shock proteins in cancer,” Cancer Letters, vol. 332, no. 2, pp. 275–285, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. C. DeBoer, P. A. Meulman, R. J. Wnuk, and D. H. Peterson, “Geldanamycin, a new antibiotic,” Journal of Antibiotics, vol. 23, no. 9, pp. 442–447, 1970. View at Publisher · View at Google Scholar · View at Scopus
  35. J. G. Supko, R. L. Hickman, M. R. Grever, and L. Malspeis, “Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent,” Cancer Chemotherapy and Pharmacology, vol. 36, no. 4, pp. 305–315, 1995. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Trepel, M. Mollapour, G. Giaccone, and L. Neckers, “Targeting the dynamic HSP90 complex in cancer,” Nature Reviews Cancer, vol. 10, no. 8, pp. 537–549, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. J. E. Lancet, I. Gojo, M. Burton et al., “Phase i study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia,” Leukemia, vol. 24, no. 4, pp. 699–705, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. P. Delmotte and J. Delmotte-Plaquee, “A new antifungal substance of fungal origin,” Nature, vol. 171, no. 4347, article 344, 1953. View at Publisher · View at Google Scholar
  39. T. W. Schulte, S. Akinaga, S. Soga et al., “Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin,” Cell Stress & Chaperones, vol. 3, no. 2, pp. 100–108, 1998. View at Google Scholar · View at Scopus
  40. P. A. Brough, W. Aherne, X. Barril et al., “4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer,” Journal of Medicinal Chemistry, vol. 51, no. 2, pp. 196–218, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. G. Chiosis, M. N. Timaul, B. Lucas et al., “A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells,” Chemistry and Biology, vol. 8, no. 3, pp. 289–299, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. E. Caldas-Lopes, L. Cerchietti, J. H. Ahn et al., “Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 20, pp. 8368–8373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. O. G. Best, N. Singh, C. Forsyth, and S. P. Mulligan, “The novel Hsp-90 inhibitor SNX7081 is significantly more potent than 17-AAG against primary CLL cells and a range of haematological cell lines, irrespective of lesions in the TP53 pathway,” British Journal of Haematology, vol. 151, no. 2, pp. 185–188, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. L. Jin, C.-L. Xiao, C.-H. Lu et al., “Transcriptomic and proteomic approach to studying SNX-2112-induced K562 cells apoptosis and anti-leukemia activity in K562-NOD/SCID mice,” FEBS Letters, vol. 583, no. 12, pp. 1859–1866, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Okawa, T. Hideshima, P. Steed et al., “SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK,” Blood, vol. 113, no. 4, pp. 846–855, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. L. Ravagnan, S. Gurbuxani, S. A. Susin et al., “Heat-shock protein 70 antagonizes apoptosis-inducing factor,” Nature Cell Biology, vol. 3, no. 9, pp. 839–843, 2001. View at Publisher · View at Google Scholar · View at Scopus
  47. J. I.-J. Leu, J. Pimkina, A. Frank, M. E. Murphy, and D. L. George, “A small molecule inhibitor of inducible heat shock protein 70,” Molecular Cell, vol. 36, no. 1, pp. 15–27, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. A. J. Massey, D. S. Williamson, H. Browne et al., “A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells,” Cancer Chemotherapy and Pharmacology, vol. 66, no. 3, pp. 535–545, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. A.-L. Rérole, J. Gobbo, A. De Thonel et al., “Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy,” Cancer Research, vol. 71, no. 2, pp. 484–495, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. E. L. Davenport, A. Zeisig, L. I. Aronson et al., “Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma,” Leukemia, vol. 24, no. 10, pp. 1804–1807, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. H. Zhang and F. Burrows, “Targeting multiple signal transduction pathways through inhibition of Hsp90,” Journal of Molecular Medicine, vol. 82, no. 8, pp. 488–499, 2004. View at Publisher · View at Google Scholar · View at Scopus
  52. N. Adhikari, N. Charles, U. Lehmann, and J. L. Hall, “Transcription factor and kinase-mediated signaling in atherosclerosis and vascular injury,” Current Atherosclerosis Reports, vol. 8, no. 3, pp. 252–260, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. A. Salminen, T. Paimela, T. Suuronen, and K. Kaarniranta, “Innate immunity meets with cellular stress at the IKK complex: regulation of the IKK complex by HSP70 and HSP90,” Immunology Letters, vol. 117, no. 1, pp. 9–15, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. V. Malhotra, T. P. Shanley, J.-F. Pittet, W. J. Welch, and H. R. Wong, “Geldanamycin inhibits NF-kappaB activation and interleukin-8 gene expression in cultured human respiratory epithelium,” American Journal of Respiratory Cell and Molecular Biology, vol. 25, no. 1, pp. 92–97, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. J. W. Rice, J. M. Veal, R. P. Fadden et al., “Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis,” Arthritis and Rheumatism, vol. 58, no. 12, pp. 3765–3775, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. J. Madrigal-Matute, O. López-Franco, L. M. Blanco-Colio et al., “Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis,” Cardiovascular Research, vol. 86, no. 2, pp. 330–337, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. G. Chen, P. Cao, and D. V. Goeddel, “TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90,” Molecular Cell, vol. 9, no. 2, pp. 401–410, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. T. J. Yun, E. K. Harning, K. Giza et al., “EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity,” Journal of Immunology, vol. 186, no. 1, pp. 563–575, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Bruemmer-Smith, F. Stüber, and S. Schroeder, “Protective functions of intracellular heat-shock protein (HSP) 70-expression in patients with severe sepsis,” Intensive Care Medicine, vol. 27, no. 12, pp. 1835–1841, 2001. View at Publisher · View at Google Scholar · View at Scopus
  60. H. Chen, Y. Wu, Y. Zhang et al., “Hsp70 inhibits lipopolysaccharide-induced NF-κB activation by interacting with TRAF6 and inhibiting its ubiquitination,” FEBS Letters, vol. 580, no. 13, pp. 3145–3152, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. F. Chalmin, S. Ladoire, G. Mignot et al., “Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells,” Journal of Clinical Investigation, vol. 120, no. 2, pp. 457–471, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. S. S. Mambula and S. K. Calderwood, “Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes,” Journal of Immunology, vol. 177, no. 11, pp. 7849–7857, 2006. View at Publisher · View at Google Scholar · View at Scopus
  63. P. Srivastava, “Roles of heat-shock proteins in innate and adaptive immunity,” Nature Reviews Immunology, vol. 2, no. 3, pp. 185–194, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Campisi, T. H. Leem, and M. Fleshner, “Stress-induced extracellular Hsp72 is a functionally significant danger signal to the immune system,” Cell Stress and Chaperones, vol. 8, no. 3, pp. 272–286, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. J. D. Johnson and M. Fleshner, “Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72,” Journal of Leukocyte Biology, vol. 79, no. 3, pp. 425–434, 2006. View at Publisher · View at Google Scholar · View at Scopus
  66. R. Njemini, M. Lambert, C. Demanet, M. V. Abeele, S. Vandebosch, and T. Mets, “The induction of heat shock protein 70 in peripheral mononuclear blood cells in elderly patients: a role for inflammatory markers,” Human Immunology, vol. 64, no. 6, pp. 575–585, 2003. View at Publisher · View at Google Scholar · View at Scopus
  67. A. G. Pockley, J. Shepherd, and J. M. Corton, “Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals,” Immunological Investigations, vol. 27, no. 6, pp. 367–377, 1998. View at Publisher · View at Google Scholar · View at Scopus
  68. T. Torigoe, Y. Tamura, and N. Sato, “Heat shock proteins and immunity: application of hyperthermia for immunomodulation,” International Journal of Hyperthermia, vol. 25, no. 8, pp. 610–616, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. A. Asea, S.-K. Kraeft, E. A. Kurt-Jones et al., “HSP70 stimulates cytokine production through a CD 14-dependant pathway, demonstrating its dual role as a chaperone and cytokine,” Nature Medicine, vol. 6, no. 4, pp. 435–442, 2000. View at Publisher · View at Google Scholar · View at Scopus
  70. W. Fiskus, S. Verstovsek, T. Manshouri et al., “Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells,” Clinical Cancer Research, vol. 17, no. 23, pp. 7347–7358, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. W. G. An, T. W. Schulte, and L. M. Neckers, “The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210(bcr-abl) and v-src proteins before their degradation by the proteasome,” Cell Growth and Differentiation, vol. 11, no. 7, pp. 355–360, 2000. View at Google Scholar · View at Scopus
  72. M. E. Gorre, K. Ellwood-Yen, G. Chiosis, N. Rosen, and C. L. Sawyers, “BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90,” Blood, vol. 100, no. 8, pp. 3041–3044, 2002. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Bareng, I. Jilani, M. Gorre et al., “A potential role for HSP90 inhibitors in the treatment of JAK2 mutant-positive diseases as demonstrated using quantitative flow cytometry,” Leukemia and Lymphoma, vol. 48, no. 11, pp. 2189–2195, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Marubayashi, P. Koppikar, T. Taldone et al., “HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans,” The Journal of Clinical Investigation, vol. 120, no. 10, pp. 3578–3593, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. L. C. Cerchietti, E. C. Lopes, S. N. Yang et al., “A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas,” Nature Medicine, vol. 15, no. 12, pp. 1369–1376, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. O. Weigert, A. A. Lane, L. Bird et al., “Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition,” Journal of Experimental Medicine, vol. 209, no. 2, pp. 259–273, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. N. Bhagwat, P. Koppikar, M. Keller et al., “Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms,” Blood, vol. 123, no. 13, pp. 2075–2083, 2014. View at Publisher · View at Google Scholar · View at Scopus
  78. T. Stühmer, A. Zöllinger, D. Siegmund et al., “Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma,” Leukemia, vol. 22, no. 8, pp. 1604–1612, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. S. A. Eccles, A. Massey, F. I. Raynaud et al., “NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis,” Cancer Research, vol. 68, no. 8, pp. 2850–2860, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. M. Kaiser, A. Kühnl, J. Reins et al., “Antileukemic activity of the HSP70 inhibitor pifithrin-l in acute leukemia,” Blood Cancer Journal, vol. 1, no. 7, article e28, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Barrio, M. Gallardo, A. Arenas et al., “Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm,” British Journal of Haematology, vol. 161, no. 5, pp. 667–676, 2013. View at Publisher · View at Google Scholar · View at Scopus