Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

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; David T. Teachey

doi:10.1182/blood-2012-03-415448

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

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, David T. Teachey

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	3510-3518
Number of pages	9
Journal	Blood
Volume	120
Issue number	17
DOIs	https://doi.org/10.1182/blood-2012-03-415448
State	Published - Oct 25 2012

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Maude, S. L., Tasian, S. K., Vincent, T., Hall, J. W., Sheen, C., Roberts, K. G., Seif, A. E., Barrett, D. M., Chen, I. M., Collins, J. R., Mullighan, C. G., Hunger, S. P., Harvey, R. C., Willman, C. L., Fridman, J. S., Loh, M. L., Grupp, S. A., & Teachey, D. T. (2012). Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood, 120(17), 3510-3518. https://doi.org/10.1182/blood-2012-03-415448

Maude, SL, Tasian, SK, Vincent, T, Hall, JW, Sheen, C, Roberts, KG, Seif, AE, Barrett, DM, Chen, IM, Collins, JR, Mullighan, CG, Hunger, SP, Harvey, RC, Willman, CL, Fridman, JS, Loh, ML, Grupp, SA & Teachey, DT 2012, 'Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia', Blood, vol. 120, no. 17, pp. 3510-3518. https://doi.org/10.1182/blood-2012-03-415448

@article{a30e8330045b4a438e423491faeb6aa3,

title = "Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia",

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.",

author = "Maude, {Shannon L.} and Tasian, {Sarah K.} and Tiffaney Vincent and Hall, {Junior W.} and Cecilia Sheen and Roberts, {Kathryn G.} and Seif, {Alix E.} and Barrett, {David M.} and Chen, {I. Ming} and Collins, {J. Racquel} and Mullighan, {Charles G.} and Hunger, {Stephen P.} and Harvey, {Richard C.} and Willman, {Cheryl L.} and Fridman, {Jordan S.} and Loh, {Mignon L.} and Grupp, {Stephan A.} and Teachey, {David T.}",

year = "2012",

month = oct,

day = "25",

doi = "10.1182/blood-2012-03-415448",

language = "English (US)",

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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.

PY - 2012/10/25

Y1 - 2012/10/25

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.

AB - 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.

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JO - Blood

JF - Blood

IS - 17

ER -

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

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