title: Combination of JAK2 and HSP90 inhibitors: an effective therapeutic option in drug-resistant chronic myelogenous leukemia.
abstract: Recent studies suggest that JAK2 serves as a novel therapeutic target in Bcr-Abl+ chronic myelogenous leukemia (CML). We have reported the existence of an HSP90- associated high molecular weight network complex (HMWNC) that is composed of HSP90 client proteins BCR-ABL, JAK2, and STAT3 in wild type Bcr-Abl+ leukemic cells. Here we showed that the HSP90-HMWNC is present in leukemia cells from CML patients in blast stage, and in Imatinib (IM)-resistant 32Dp210 (T315I) leukemia cells. We found that the HSP90-HMWNC could be disassembled by depleting JAK2 with either Jak2-specific shRNA or treatment with JAK2 inhibitors (TG101209 or Ruxolitinib) and HSP90 inhibitor (AUY922). Combinational treatment with JAK2 and HSP90 inhibitors diminished the activation of BCR-ABL, JAK2 and its downstream targets. As a result, the IM-resistant 32Dp210 T315I cells underwent apoptosis. When administered in mice bearing 32Dp210 T315I leukemia, combinational therapy using Ruxolitinib and AUY922 prolonged the survival significantly. Thus, a combination of JAK2 and HSP90 inhibitors could be a powerful strategy for the treatment of CML, especially in IM-resistant patients.
authors.affiliation: Department of Translational Molecular Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Sandip N
authors.initials: SN
authors.lastname: Chakraborty
authors.affiliation: Department of Translational Molecular Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Translational Molecular Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Bastianella
authors.initials: B
authors.lastname: Perazzona
authors.affiliation: Department of Laboratory Medicine, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Translational Molecular Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Yu-Hsi
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Translational Molecular Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Arlinghaus
keywords: Bcr-Abl; CML; HSP90; JAK2; drug-resistance; network complex