Tags

Type your tag names separated by a space and hit enter

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.
Blood 2012; 120(17):3510-8Blood

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.

Authors+Show Affiliations

Division of Oncology, The Children's Hospital of Philadelphia, PA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22955920

Citation

Maude, Shannon L., et al. "Targeting JAK1/2 and mTOR in Murine Xenograft Models of Ph-like Acute Lymphoblastic Leukemia." Blood, vol. 120, no. 17, 2012, pp. 3510-8.
Maude SL, Tasian SK, Vincent T, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510-8.
Maude, S. L., Tasian, S. K., Vincent, T., Hall, J. W., Sheen, C., Roberts, K. G., ... Teachey, D. T. (2012). Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood, 120(17), pp. 3510-8. doi:10.1182/blood-2012-03-415448.
Maude SL, et al. Targeting JAK1/2 and mTOR in Murine Xenograft Models of Ph-like Acute Lymphoblastic Leukemia. Blood. 2012 Oct 25;120(17):3510-8. PubMed PMID: 22955920.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. AU - Maude,Shannon L, AU - Tasian,Sarah K, AU - Vincent,Tiffaney, AU - Hall,Junior W, AU - Sheen,Cecilia, AU - Roberts,Kathryn G, AU - Seif,Alix E, AU - Barrett,David M, AU - Chen,I-Ming, AU - Collins,J Racquel, AU - Mullighan,Charles G, AU - Hunger,Stephen P, AU - Harvey,Richard C, AU - Willman,Cheryl L, AU - Fridman,Jordan S, AU - Loh,Mignon L, AU - Grupp,Stephan A, AU - Teachey,David T, Y1 - 2012/09/06/ PY - 2012/9/8/entrez PY - 2012/9/8/pubmed PY - 2013/1/4/medline SP - 3510 EP - 8 JF - Blood JO - Blood VL - 120 IS - 17 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/22955920/Targeting_JAK1/2_and_mTOR_in_murine_xenograft_models_of_Ph_like_acute_lymphoblastic_leukemia_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&amp;pmid=22955920 DB - PRIME DP - Unbound Medicine ER -