Abstract
Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin-Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cathepsin G / genetics
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Cell Line, Tumor
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Disease Models, Animal
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Female
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / metabolism*
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Leukemia, Promyelocytic, Acute / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Oncogene Proteins, Fusion / genetics
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction / genetics
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Signal Transduction / physiology*
Substances
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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NOTCH1 protein, human
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Notch1 protein, mouse
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Oncogene Proteins, Fusion
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Receptor, Notch1
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Serrate-Jagged Proteins
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Cathepsin G
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Ctsg protein, mouse