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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.
Oncotarget 2018; 9(8):8027-8041O

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.

Authors+Show Affiliations

Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Department of Hematology, The First Hospital Affiliated Harbin Medical University, Harbin, China.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Department of Hematology, The First Hospital Affiliated Harbin Medical University, Harbin, China.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Next Generation Hematology Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Bioinformatics & Comp Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Bioinformatics & Comp Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA, USA.Department of Hematology, The First Hospital Affiliated Harbin Medical University, Harbin, China.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Department of Hematology, The First Hospital Affiliated Harbin Medical University, Harbin, China.Department of Leukemia, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA, USA.Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA.Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29487712

Citation

Zhang, Qi, et al. "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." Oncotarget, vol. 9, no. 8, 2018, pp. 8027-8041.
Zhang Q, Shi C, Han L, et al. 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. Oncotarget. 2018;9(8):8027-8041.
Zhang, Q., Shi, C., Han, L., Jain, N., Roberts, K. G., Ma, H., ... Konopleva, M. (2018). 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. Oncotarget, 9(8), pp. 8027-8041. doi:10.18632/oncotarget.24261.
Zhang Q, et al. 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. Oncotarget. 2018 Jan 30;9(8):8027-8041. PubMed PMID: 29487712.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Zhang,Qi, AU - Shi,Ce, AU - Han,Lina, AU - Jain,Nitin, AU - Roberts,Kathryn G, AU - Ma,Helen, AU - Cai,Tianyu, AU - Cavazos,Antonio, AU - Tabe,Yoko, AU - Jacamo,Rodrigo O, AU - Mu,Hong, AU - Zhao,Yang, AU - Wang,Jing, AU - Wu,Shuo-Chieh, AU - Cao,Fenglin, AU - Zeng,Zhihong, AU - Zhou,Jin, AU - Mi,Yingchang, AU - Jabbour,Elias J, AU - Levine,Ross, AU - Tasian,Sarah K, AU - Mullighan,Charles G, AU - Weinstock,David M, AU - Fruman,David A, AU - Konopleva,Marina, Y1 - 2018/01/17/ PY - 2018/01/03/received PY - 2018/01/09/accepted PY - 2018/3/1/entrez PY - 2018/3/1/pubmed PY - 2018/3/1/medline KW - JAK KW - Ph-like ALL KW - mTOR SP - 8027 EP - 8041 JF - Oncotarget JO - Oncotarget VL - 9 IS - 8 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/29487712/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_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=24261 DB - PRIME DP - Unbound Medicine ER -