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.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, PA, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Maude
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.forename: Tiffaney
authors.initials: T
authors.lastname: Vincent
authors.forename: Junior W
authors.initials: JW
authors.lastname: Hall
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sheen
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Roberts
authors.forename: Alix E
authors.initials: AE
authors.lastname: Seif
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: J Racquel
authors.initials: JR
authors.lastname: Collins
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
mesh_terms: D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002648:Child; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D009570:Nitriles; D010677:Philadelphia Chromosome; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007136:Immunoglobulins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D018121:Receptors, Cytokine; D050799:STAT5 Transcription Factor; C410591:Tslpr protein, mouse; C540383:ruxolitinib; C546843:mTOR protein, mouse; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus