title: Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412.
abstract: MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In the present study, we examined the expression and functional role of MCL-1 in neoplastic MCs and sought to determine whether MCL-1 could serve as a target in SM. As assessed by RT-PCR and immunohistochemical examination, primary neoplastic MCs expressed MCL-1 mRNA and the MCL-1 protein in all SM patients examined. Moreover, MCL-1 was detectable in both subclones of the MC line HMC-1--HMC-1.1 cells, which lack the SM-related KIT mutation D816V, and HMC-1.2 cells, which carry KIT D816V. Exposure of HMC-1.1 cells or HMC-1.2 cells to MCL-1-specific antisense oligonucleotides (ASOs) or MCL-1-specific siRNA resulted in reduced survival and increased apoptosis compared with untreated cells. Moreover, MCL-1 ASOs were found to cooperate with various tyrosine kinase inhibitors in producing growth inhibition in neoplastic MCs, with synergistic effects observed with PKC412, AMN107, and imatinib in HMC-1.1 cells and with PKC412 in HMC-1.2 cells. Together, these data show that MCL-1 is a novel survival factor and an attractive target in neoplastic MCs.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Aichberger
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Maria-Theresa
authors.initials: MT
authors.lastname: Krauth
authors.forename: Alexander
authors.initials: A
authors.lastname: Gruze
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
authors.forename: Hermine
authors.initials: H
authors.lastname: Agis
authors.forename: Christian
authors.initials: C
authors.lastname: Sillaber
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001483:Base Sequence; D001549:Benzamides; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D020320:Oligoribonucleotides, Antisense; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D011493:Protein Kinase C; C498826:nilotinib; D019311:Staurosporine; C059539:midostaurin