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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Antineoplastic Agents / administration & dosage
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Base Sequence
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Benzamides
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Cell Line
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DNA Primers / genetics
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Drug Synergism
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Female
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Humans
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Imatinib Mesylate
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In Vitro Techniques
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Male
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Mast Cells / drug effects*
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Mast Cells / pathology
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Mastocytosis, Systemic / drug therapy*
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Mastocytosis, Systemic / genetics
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Mastocytosis, Systemic / metabolism
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Mastocytosis, Systemic / pathology
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Mastocytosis, Systemic / therapy*
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Middle Aged
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Oligoribonucleotides, Antisense / administration & dosage
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Oligoribonucleotides, Antisense / genetics
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Oligoribonucleotides, Antisense / pharmacology*
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Piperazines / administration & dosage
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase Inhibitors / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Pyrimidines / administration & dosage
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RNA, Small Interfering / genetics
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Staurosporine / administration & dosage
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Staurosporine / analogs & derivatives*
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Transfection
Substances
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Antineoplastic Agents
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Benzamides
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DNA Primers
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Oligoribonucleotides, Antisense
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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RNA, Small Interfering
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Imatinib Mesylate
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Proto-Oncogene Proteins c-kit
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Protein Kinase C
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nilotinib
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Staurosporine
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midostaurin