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
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Qi Zhang1,*, Ce Shi1,6,*, Lina Han1,6, Nitin Jain1, Kathryn G. Roberts2, Helen Ma1, Tianyu Cai1, Antonio Cavazos1, Yoko Tabe3, Rodrigo O. Jacamo1, Hong Mu1, Yang Zhao4, Jing Wang4, Shuo-Chieh Wu5, Fenglin Cao6, Zhihong Zeng1, Jin Zhou6, Yingchang Mi7, Elias J. Jabbour1, Ross Levine8, Sarah K. Tasian9, Charles G. Mullighan2, David M. Weinstock5, David A. Fruman10 and Marina Konopleva1
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
2Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
3Department of Next Generation Hematology Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan
4Department of Bioinformatics & Comp Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
5Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA, USA
6Department of Hematology, The First Hospital Affiliated Harbin Medical University, Harbin, China
7Department of Leukemia, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China
8Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
9Division of Oncology and Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
10Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA
*These authors have contributed equally to this work
Marina Konopleva, email: [email protected]
Keywords: Ph-like ALL; JAK; mTOR
Received: January 03, 2018 Accepted: January 09, 2018 Published: January 17, 2018
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)  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.
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