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https://hdl.handle.net/2440/103604
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Type: | Journal article |
Title: | Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia |
Author: | Maude, S. Tasian, S. Vincent, T. Hall, J. Sheen, C. Roberts, K. Seif, A. Barrett, D. Chen, I. Collins, J. Mullighan, C. Hunger, S. Harvey, R. Willman, C. Fridman, J. Loh, M. Grupp, S. Teachey, D. |
Citation: | Blood, 2012; 120(17):3510-3518 |
Publisher: | American Society of Hematology |
Issue Date: | 2012 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Shannon L. Maude, Sarah K. Tasian, Tiffaney Vincent, Junior W. Hall, Cecilia Sheen, Kathryn G. Roberts, Alix E. Seif, David M. Barrett, I-Ming Chen, J. Racquel Collins, Charles G. Mullighan, Stephen P. Hunger, Richard C. Harvey, Cheryl L. Willman, Jordan S. Fridman, Mignon L. Loh, Stephan A. Grupp, and David T. Teachey |
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. |
Keywords: | JAK1/2; Mtor; leukemia |
Rights: | © 2012 by The American Society of Hematology |
DOI: | 10.1182/blood-2012-03-415448 |
Published version: | http://dx.doi.org/10.1182/blood-2012-03-415448 |
Appears in Collections: | Aurora harvest 3 Molecular and Biomedical Science publications |
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