title: Plasma Hsp90 Level as a Marker of Early Acute Lymphoblastic Leukemia Engraftment and Progression in Mice.
abstract: Current monitoring of acute lymphoblastic leukemia (ALL) in living mice is based on FACS analysis of blood hCD45+ cells. In this work, we evaluated the use of human IGFBP2, B2M or Hsp90 as soluble markers of leukemia. ELISA for B2M and IGFBP2 resulted in high background levels in healthy animals, precluding its use. Conversely, plasma levels of Hsp90 showed low background and linear correlation to FACS results. In another experiment, we compared Hsp90 levels with percentage of hCD45+ cells in blood, bone marrow, liver and spleen of animals weekly sacrificed. Hsp90 levels proved to be a superior method for the earlier detection of ALL engraftment and correlated linearly to ALL burden and progression in all compartments, even at minimal residual disease levels. Importantly, the Hsp90/hCD45+ ratio was not altered when animals were treated with dexamethasone or a PI3K inhibitor, indicating that chemotherapy does not directly interfere with leukemia production of Hsp90. In conclusion, plasma Hsp90 was validated as a soluble biomarker of ALL, useful for earlier detection of leukemia engraftment, monitoring leukemia kinetics at residual disease levels, and pre-clinical or mouse avatar evaluations of anti-leukemic drugs.
authors.affiliation: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: Mateus
authors.initials: M
authors.lastname: Milani
authors.affiliation: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: Angelo Brunelli Albertoni
authors.initials: AB
authors.lastname: Laranjeira
authors.affiliation: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: Jaíra Ferreira
authors.initials: JF
authors.lastname: de Vasconcellos
authors.affiliation: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.affiliation: Centro Integrado de Pesquisas Oncohematologicas da Infância (CIPOI), Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Alexandre Eduardo
authors.initials: AE
authors.lastname: Nowill
authors.affiliation: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil; Departamento de Genética Médica, FCM, UNICAMP, Campinas, SP, Brazil.
authors.forename: José Andrés
authors.initials: JA
authors.lastname: Yunes
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D003907:Dexamethasone / Q000627:therapeutic use; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000097:blood*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D003907:Dexamethasone; D018841:HSP90 Heat-Shock Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D017493:Leukocyte Common Antigens; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors