Oncotarget

Research Papers:

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

Qi Zhang, Ce Shi, Lina Han, Nitin Jain, Kathryn G. Roberts, Helen Ma, Tianyu Cai, Antonio Cavazos, Yoko Tabe, Rodrigo O. Jacamo, Hong Mu, Yang Zhao, Jing Wang, Shuo-Chieh Wu, Fenglin Cao, Zhihong Zeng, Jin Zhou, Yingchang Mi, Elias J. Jabbour, Ross Levine, Sarah K. Tasian, Charles G. Mullighan, David M. Weinstock, David A. Fruman and Marina Konopleva _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:8027-8041. https://doi.org/10.18632/oncotarget.24261

Metrics: PDF 1362 views  |   HTML 2109 views  |   ?  


Abstract

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

Correspondence to:

Marina Konopleva, email: mkonople@mdanderson.org

Keywords: Ph-like ALL; JAK; mTOR

Received: January 03, 2018     Accepted: January 09, 2018     Published: January 17, 2018

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 24261