Abstract
Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.
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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Adolescent
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Adult
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Aminopyridines / pharmacology
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Anaplastic Lymphoma Kinase / genetics*
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Benzothiazoles / pharmacology
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Child
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Child, Preschool
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Exome Sequencing
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Female
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Genome, Human
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Hematologic Neoplasms / drug therapy
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Hematologic Neoplasms / genetics
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Hematologic Neoplasms / pathology
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Histiocytosis / drug therapy
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Histiocytosis / genetics*
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Histiocytosis / pathology
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Humans
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Infant
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Male
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Mutation
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Picolinic Acids / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-ret / genetics*
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Pyrroles / pharmacology
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Receptor Protein-Tyrosine Kinases / genetics
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
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Twins, Monozygotic
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Young Adult
Substances
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4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide
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Aminopyridines
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Benzothiazoles
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CSF1R protein, human
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Picolinic Acids
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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Pyrroles
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
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pexidartinib
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selpercatinib
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ALK protein, human
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Anaplastic Lymphoma Kinase
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Proto-Oncogene Proteins c-ret
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RET protein, human
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Receptor Protein-Tyrosine Kinases