title: Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells.
abstract: Systemic mastocytosis (SM) is a myeloid neoplasm characterized by increased survival and accumulation of neoplastic mast cells (MCs). In most patients, the D816V-mutated variant of KIT is detectable. We report here that heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a novel KIT-inducible survival factor in neoplastic MCs. As assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and Western blotting, the KIT D816V(+) MC line HMC-1.2 as well as highly enriched primary neoplastic MCs were found to express Hsp32 mRNA and the Hsp32 protein. Moreover, KIT D816V and stem cell factor (SCF)-activated wild-type KIT were found to induce Hsp32 promoter activity, expression of Hsp32 mRNA, and expression of the Hsp32 protein in Ba/F3 cells. Correspondingly, the KIT D816V-targeting drug PKC412 decreased the expression of Hsp32 as well as proliferation/survival in neoplastic MCs. The inhibitory effects of PKC412 on the survival of HMC-1.2 cells were counteracted by the HO-1 inductor hemin or lentiviral-transduced HO-1. Moreover, 2 Hsp32-targeting drugs, pegylated zinc protoporphyrin (PEG-ZnPP) and styrene maleic acid copolymer micelle-encapsulated ZnPP (SMA-ZnPP), were found to inhibit proliferation and to induce apoptosis in neoplastic MCs. Furthermore, both drugs were found to cooperate with PKC412 in producing growth inhibition. Together, these data show that Hsp32 is an important survival factor and interesting new therapeutic target in neoplastic MCs.
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Rudin
authors.initials: R
authors.lastname: Kondo
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: Anja
authors.initials: A
authors.lastname: Vales
authors.forename: Alexander
authors.initials: A
authors.lastname: Gruze
authors.forename: Puchit
authors.initials: P
authors.lastname: Samorapoompichit
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.forename: Maria-Theresa
authors.initials: MT
authors.lastname: Krauth
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Aichberger
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Christian
authors.initials: C
authors.lastname: Sillaber
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004318:Doxycycline / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D004318:Doxycycline; D013936:Thymidine