title: HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment.
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.
authors.affiliation: Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago and.
authors.forename: A
authors.initials: A
authors.lastname: Guo
authors.affiliation: Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago and.
authors.forename: P
authors.initials: P
authors.lastname: Lu
authors.affiliation: Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago and.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago and.
authors.forename: C
authors.initials: C
authors.lastname: Zhen
authors.affiliation: Program in Chemical Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago and.
authors.forename: Y L
authors.initials: YL
authors.lastname: Wang
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D052117:Benzodioxoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D000072377:Syk Kinase / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt