Abstract
CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.
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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Acute Disease
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Animals
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Antineoplastic Agents / pharmacology*
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Child
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunoglobulins / genetics
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Immunoglobulins / metabolism
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Janus Kinase 1 / antagonists & inhibitors*
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Janus Kinase 1 / genetics
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Janus Kinase 1 / metabolism
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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Mice
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Molecular Targeted Therapy
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Nitriles
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Philadelphia Chromosome
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Protein Kinase Inhibitors / pharmacology*
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Pyrazoles / pharmacology*
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Pyrimidines
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Receptors, Cytokine / genetics
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Receptors, Cytokine / metabolism
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sirolimus / pharmacology*
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Survival Rate
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Immunoglobulins
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Nitriles
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Receptors, Cytokine
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STAT5 Transcription Factor
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Tslpr protein, mouse
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ruxolitinib
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mTOR protein, mouse
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Jak1 protein, mouse
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Jak2 protein, mouse
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Janus Kinase 1
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Janus Kinase 2
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TOR Serine-Threonine Kinases
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Sirolimus