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

被引：227

作者：

Maude, Shannon L. ^{[1
,2
]}

Tasian, Sarah K. ^{[1
,2
]}

Vincent, Tiffaney ^{[1
]}

Hall, Junior W. ^{[1
]}

Sheen, Cecilia ^{[1
]}

Roberts, Kathryn G. ^{[3
]}

Seif, Alix E. ^{[1
,2
]}

Barrett, David M. ^{[1
,2
]}

Chen, I-Ming ^{[4
]}

Collins, J. Racquel ^{[3
]}

Mullighan, Charles G. ^{[3
]}

Hunger, Stephen P. ^{[5
]}

Harvey, Richard C. ^{[4
]}

Willman, Cheryl L. ^{[4
]}

Fridman, Jordan S. ^{[6
]}

Loh, Mignon L. ^{[7
]}

Grupp, Stephan A. ^{[1
,2
]}

Teachey, David T. ^{[1
,2
]}

机构：

[1] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[4] Univ New Mexico, Ctr Canc, UNM Canc Res Facil, Albuquerque, NM 87131 USA

[5] Univ Colorado, Sch Med, Pediat Hematol Oncol BMT, Aurora, CO USA

[6] Incyte Corp, Wilmington, DE USA

[7] Univ Calif San Francisco, Div Pediat Hematol Oncol, San Francisco, CA 94143 USA

来源：

BLOOD | 2012年 / 120卷 / 17期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

OF-FUNCTION MUTATIONS; MAMMALIAN TARGET; GENETIC ALTERATIONS; STAT5; ACTIVATION; ABERRANT STAT5; B-PROGENITOR; IN-VITRO; RAPAMYCIN; RECEPTOR; CRLF2;

D O I：

10.1182/blood-2012-03-415448

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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)

引用

页码：3510 / 3518

页数：9

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