Mechanisms of disease

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Mechanisms of disease

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Together with our numerous collaborators, we have been and continue to use these CSC-directed chemical tools to understand the complex proteome alterations that occur in specific chronically stressed cells/organisms such as in cancer, neurodegenerative diseases and microorganisms living in conditions of stress. Examples are the discovery of mechanisms behind: transforming ability of BCL6 in a subset of BCL6-driven Diffuse Large B-Cell Lymphomas (DLBCL) [Nature Medicine 2009] (collaboration with A. Melnick lab); regulation of apoptosis in small-cell lung carcinomas [Nature Chem Biol 2007] (collaboration with Jiang and Massague labs); the altered proteome and its addiction to tumor HSP90 in a subset of triple negative breast cancer [PNAS 2009]; regulation of HER2 activity in HER2 overexpressing breast cancers [Nature Chem Biol 2013]; transformation in JAK2-driven MPDs and potential mechanisms associated with resistance to JAK inhibitors [J Clinical Investigation 2010, Nature 2012, Blood 2014]; (collaboration with R. Levine lab); regulation of the viral oncoproteome in Kaposi sarcoma herpes virus (KHSV)-associated lymphomas [Blood 2013]; (collaboration with E. Cesarman lab); regulation of the activated STAT5 signaling and increased transcriptional activity in chronic myeloid leukemia [Nature Chem Biol 2011]; molecular signature of HSP90-addicted AML [Cell Reports 2015] (collaboration with M Guzman lab); the biochemical nature of the CSC/epichaperome networks in cancer and their therapeutic implications (interdisciplinary multimember team Nature 2016 and Nature Medicine 2018); the nature of CSC networks in PD neurons (Nature Communications 2018, collaboration with Studer lab) to list a few.

  1. Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016;538(7625):397-401. PMCID: PMC5283383. Altmetric 439 PubMed
  2. Kishinevsky S, Wang T, Rodina A, Chung SY, Xu C, Philip J, Taldone T, Joshi S, Alpaugh ML, Bolaender A, Gutbier S, Sandhu D, Fattahi F, Zimmer B, Shah SK, Chang E, Inda C, Koren J, Saurat NG, Leist M, Gross SS, Seshan VE, Klein C, Tomishima MJ, Erdjument-Bromage H, Neubert TA, Henrickson RC, Chiosis G, Studer L. HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nature Communications. 2018;9(1):4345. 
  3. Kourtis N, Lazaris C, Hockemeyer K, Balandran JC, Jimenez AR, Mullenders J, Gong Y, Trimarchi T, Bhatt K, Hu H, Shrestha L, Ambesi-Impiombato A, Kelliher M, Paietta E, Chiosis G, Guzman ML, Ferrando AA, Tsirigos A, Aifantis I. Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Nat Med. 2018;24(8):1157-66. PMCID: PMC6082694. Altmetric 462. PubMed
  4. Zong H, Gozman A, Caldas-Lopes E, Taldone T, Sturgill E, Brennan S, Ochiana SO, Gomes-DaGama EM, Sen S, Rodina A, Koren J, 3rd, Becker MW, Rudin CM, Melnick A, Levine RL, Roboz GJ, Nimer SD, Chiosis G, Guzman ML. A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. Cell Rep. 2015;13(10):2159-73. PMCID: PMC4699804. PubMed [PMID: 26628369] 
  5. Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N, Caldas-Lopes E, Ross KN, Gonen M, Gozman A, Ahn JH, Rodina A, Ouerfelli O, Yang G, Hedvat C, Bradner JE, Chiosis G, Levine RL. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010;120(10):3578-93. PMCID: PMC2947224. PubMed
  6. Cerchietti LC, Hatzi K, Caldas-Lopes E, Yang SN, Figueroa ME, Morin RD, Hirst M, Mendez L, Shaknovich R, Cole PA, Bhalla K, Gascoyne RD, Marra M, Chiosis G, Melnick A. BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. J Clin Invest. 2010;120(12):4569-82. PMCID: PMC2993589. PubMed
  7. Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, Liu F, Saunders LM, Mullally A, Abdel-Wahab O, Leung L, Weinstein A, Marubayashi S, Goel A, Gonen M, Estrov Z, Ebert BL, Chiosis G, Nimer SD, Bernstein BE, Verstovsek S, Levine RL. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155-9. PMCID: PMC3991463. PubMed
  8. Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol. 2013;9(11):677-84. PMCID: PMC3982621. PubMed
  9. Nayar U, Lu P, Goldstein RL, Vider J, Ballon G, Rodina A, Taldone T, Erdjument-Bromage H, Chomet M, Blasberg R, Melnick A, Cerchietti L, Chiosis G, Wang YL, Cesarman E. Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood. 2013;122(16):2837-47. PMCID: PMC3798998. PubMed
  10. Ambati SR, Lopes EC, Kosugi K, Mony U, Zehir A, Shah SK, Taldone T, Moreira AL, Meyers PA, Chiosis G, Moore MA. Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma. Mol Oncol. 2014;8(2):323-36. PMCID: PMC3982393. PubMed
  11. Bhagwat N, Koppikar P, Keller M, Marubayashi S, Shank K, Rampal R, Qi J, Kleppe M, Patel HJ, Shah SK, Taldone T, Bradner JE, Chiosis G, Levine RL. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014;123(13):2075-83. PMCID: PMC3968390. PubMed
  12. Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, Otto GA, Yelensky R, Hricik T, McKenney AS, Chiosis G, Chung YR, Pandey S, van den Brink MR, Armstrong SA, Dogan A, Intlekofer A, Manshouri T, Park CY, Verstovsek S, Rapaport F, Stephens PJ, Miller VA, Levine RL. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014;111(50):E5401-10. PMCID: PMC4273376. PubMed
  13. Kucine N, Marubayashi S, Bhagwat N, Papalexi E, Koppikar P, Sanchez Martin M, Dong L, Tallman MS, Paietta E, Wang K, He J, Lipson D, Stephens P, Miller V, Rowe JM, Teruya-Feldstein J, Mullighan CG, Ferrando AA, Krivtsov A, Armstrong S, Leung L, Ochiana SO, Chiosis G, Levine RL, Kleppe M. Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias. Blood. 2015;126(22):2479-83. PMCID: PMC4661170. PubMed
  14. Goldstein RL, Yang SN, Taldone T, Chang B, Gerecitano J, Elenitoba-Johnson K, Shaknovich R, Tam W, Leonard JP, Chiosis G, Cerchietti L, Melnick A. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J Clin Invest. 2015;125(12):4559-71. PMCID: PMC4665772. PubMed
  15. Culjkovic-Kraljacic B, Fernando TM, Marullo R, Calvo-Vidal N, Verma A, Yang S, Tabbo F, Gaudiano M, Zahreddine H, Goldstein RL, Patel J, Taldone T, Chiosis G, Ladetto M, Ghione P, Machiorlatti R, Elemento O, Inghirami G, Melnick A, Borden KL, Cerchietti L. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood. 2016;127(7):858-68. PMCID: PMC4760090. PubMed
  16. Guo A, Lu P, Lee J, Zhen C, Chiosis G, Wang YL. HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene. 2017;36(24):3441-9. PMCID: PMC5645670. PubMed
  17. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA, Mallik A, Robles AI, Walling J, Varticovski L, Shaknovich R, Bhalla KN, Chiosis G, Melnick A. Nat Med. 2009 Dec;15(12):1369-76.
  18. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models.Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G.Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73.

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