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.

journal_name

Blood

journal_title

Blood

authors

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

doi

10.1182/blood-2012-03-415448

subject

Has Abstract

pub_date

2012-10-25 00:00:00

pages

3510-8

issue

17

eissn

0006-4971

issn

1528-0020

pii

blood-2012-03-415448

journal_volume

120

pub_type

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