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Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in CRLF2 rearranged and/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia.


ABSTRACT: Patients with cytokine receptor-like factor 2 rearranged (CRLF2-re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. CRFL2-re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in CRLF2-re Ph-like B-ALL. In this study, we tested the antileukemia efficacy of the type I JAK inhibitor ruxolitinib and type II JAK inhibitor NVP-BBT594 (hereafter abbreviated BBT594) [1] alone and combined with allosteric mTOR inhibitor rapamycin and a second generation ATP-competitive mTOR kinase inhibitor AZD2014. We found that BBT594/AZD2014 combination produced robust anti-leukemic effects in Ph-like cell lines in vitro and in patient-derived xenograft (PDX) cells cultured ex vivo. JAK2/mTOR inhibition arrested the cell cycle and reduced cell survival to a greater extent in Ph-like B-ALL cells with CRLF2-re and JAK2 mutation. Synergistic cell killing was associated with the greater inhibition of JAK2 phosphorylation by BBT594 than by ruxolitinib and the greater inhibition of AKT and 4E-BP1 phosphorylation by AZD2014 than by rapamycin. In vivo, BBT594/AZD2014 co-treatment was most efficacious in reducing spleen size in three Ph-like PDX models, and markedly depleted bone marrow and spleen ALL cells in an ATF7IP-JAK2 fusion PDX. In summary, combined inhibition of JAK/STAT and mTOR pathways by next-generation inhibitors had promising antileukemia efficacy in preclinical models of CRFL2-re Ph-like B-ALL.

SUBMITTER: Zhang Q 

PROVIDER: S-EPMC5814279 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in <i>CRLF2</i> rearranged and/or <i>JAK</i> driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia.

Zhang Qi Q   Shi Ce C   Han Lina L   Jain Nitin N   Roberts Kathryn G KG   Ma Helen H   Cai Tianyu T   Cavazos Antonio A   Tabe Yoko Y   Jacamo Rodrigo O RO   Mu Hong H   Zhao Yang Y   Wang Jing J   Wu Shuo-Chieh SC   Cao Fenglin F   Zeng Zhihong Z   Zhou Jin J   Mi Yingchang Y   Jabbour Elias J EJ   Levine Ross R   Tasian Sarah K SK   Mullighan Charles G CG   Weinstock David M DM   Fruman David A DA   Konopleva Marina M  

Oncotarget 20180117 8


Patients with cytokine receptor-like factor 2 rearranged (<i>CRLF2</i>-re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. <i>CRFL2</i>-re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in <i>CRL  ...[more]

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