期刊
BLOOD
卷 120, 期 17, 页码 3510-3518出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-03-415448
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资金
- National Institutes of Health [CA102646, CA1116660, R56A1099301]
- Leukemia & Lymphoma Society
- Patient Impact Initiative
- Larry and Helen Hoag Foundation Clinical Translational Research Career Development Award
- American Cancer Society [RSG0507101]
- Children's Hospital of Philadelphia
- University of Pennsylvania Cancer Research Training Program National Research Service Award [T32CA009615-21]
- When Everyone Survives Foundation
- Abramson Cancer Center's Paul Calabresi Career Development Award [K12CA076931]
- Conquer Cancer Foundation/American Society of Clinical Oncology Young Investigator Award
- Alex's Lemonade Stand Foundation Young InvestigatorAward
- National Health and Medical Research Council of Australia
- American Lebanese and Syrian Associated Charities of St Jude Children's Research Hospital
- Stand Up To Cancer Innovative Research Grant
- St Baldrick's Research Grant
- COG Chair's grant [CA98543]
- COG Statistical Center [U10 CA98413]
- COG Specimen Banking [U24 CA114766]
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. (Blood. 2012;120(17):3510-3518)
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