title: Identification of heat shock protein 32 (Hsp32) as a novel target in acute lymphoblastic leukemia.
abstract: Heat shock proteins (Hsp) are increasingly employed as therapeutic targets in oncology. We have shown that Hsp32, also known as heme oxygenase-1 (HO-1), serves as survival factor and potential target in Ph+ chronic myeloid leukemia. We here report that primary cells and cell lines derived from patients with acute lymphoblastic leukemia (ALL) express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Highly enriched CD34+/CD38- ALL stem cells also expressed Hsp32. Two Hsp32-targeting drugs, pegylated zinc protoporphyrine (PEG-ZnPP) and styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP), induced apoptosis and growth arrest in the BCR/ABL1+ cell lines, in Ph- lymphoblastic cell lines and in primary Ph+ and Ph- ALL cells. The effects of PEG-ZnPP and SMA-ZnPP on growth of leukemic cells were dose-dependent. In Ph+ ALL, major growth-inhibitory effects of the Hsp32-targeting drugs were observed in imatinib-sensitive and imatinib-resistant cells. Hsp32-targeting drugs were found to synergize with imatinib, nilotinib, and bendamustine in producing growth inhibition and apoptosis in Ph+ ALL cells. A siRNA against Hsp32 was found to inhibit growth and survival of ALL cells and to synergize with imatinib in suppressing the growth of ALL cells. In conclusion, Hsp32 is an essential survival factor and potential new target in ALL.
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: Renata A
authors.initials: RA
authors.lastname: Meyer
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stefanzl
authors.forename: Emir
authors.initials: E
authors.lastname: Hadzijusufovic
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000069461:Bendamustine Hydrochloride; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008298:Maleates / Q000494:pharmacology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011137:Polystyrenes / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D001549:Benzamides; D008298:Maleates; D008665:Metalloporphyrins; D009588:Nitrogen Mustard Compounds; D010879:Piperazines; D011137:Polystyrenes; D011743:Pyrimidines; D012333:RNA, Messenger; C518727:copoly(styrene-maleic acid)-zinc protoporphyrin; C476103:pegylated zinc protoporphyrin; D011092:Polyethylene Glycols; D000068877:Imatinib Mesylate; D000069461:Bendamustine Hydrochloride; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib