Abstract
The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells.
© 2015 by The American Society of Hematology.
Publication types
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Clinical Trial
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Multicenter Study
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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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Benzodioxoles / pharmacology*
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Female
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HSP90 Heat-Shock Proteins* / antagonists & inhibitors
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HSP90 Heat-Shock Proteins* / genetics
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HSP90 Heat-Shock Proteins* / metabolism
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Humans
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Janus Kinase 1* / genetics
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Janus Kinase 1* / metabolism
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Janus Kinase 2* / genetics
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Janus Kinase 2* / metabolism
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Male
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Mice
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Mutation
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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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Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma* / pathology
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Purines / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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Benzodioxoles
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HSP90 Heat-Shock Proteins
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Neoplasm Proteins
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Purines
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9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
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JAK1 protein, human
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JAK2 protein, human
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Janus Kinase 1
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Janus Kinase 2