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Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2.
Oncotarget 2018; 9(42):26834-26851O

Abstract

The activated JAK2-V617F mutant is very frequently found in myeloproliferative neoplasms (MPNs), and its inhibitor ruxolitinib has been in clinical use, albeit with limited efficacies. Here, we examine the signaling mechanisms from JAK2-V617F and responses to ruxolitinib in JAK2-V617F-positive leukemic cell lines, including PVTL-2, newly established from a patient with post-MPN secondary acute myeloid leukemia, and the widely used model cell line HEL. We have found that ruxolitinib downregulated the mTORC1/S6K/4EBP1 pathway at least partly through inhibition of the STAT5/Pim-2 pathway with concomitant downregulation of c-Myc, MCL-1, and BCL-xL as well as induction of autophagy in these cells. Ruxolitinib very efficiently inhibited proliferation but only modestly induced apoptosis. However, inhibition of BCL-xL/BCL-2 by the BH3 mimetics ABT-737 and navitoclax or BCL-xL by A-1331852 induced caspase-dependent apoptosis involving activation of Bak and Bax synergistically with ruxolitinib in HEL cells. On the other hand, the putative pan-BH3 mimetic obatoclax as well as chloroquine and bafilomycin A1 inhibited autophagy at its late stage and induced apoptosis in PVTL-2 cells synergistically with ruxolitinib. The present study suggests that autophagy as well as the anti-apoptotic BCL-2 family members, regulated at least partly by the mTORC1 pathway downstream of STAT5/Pim-2, protects JAK2-V617F-positive leukemic cells from ruxolitinib-induced apoptosis depending on cell types and may contribute to development of new strategies against JAK2-V617F-positive neoplasms.

Authors+Show Affiliations

Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29928488

Citation

Ishida, Shinya, et al. "Mechanisms for mTORC1 Activation and Synergistic Induction of Apoptosis By Ruxolitinib and BH3 Mimetics or Autophagy Inhibitors in JAK2-V617F-expressing Leukemic Cells Including Newly Established PVTL-2." Oncotarget, vol. 9, no. 42, 2018, pp. 26834-26851.
Ishida S, Akiyama H, Umezawa Y, et al. Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2. Oncotarget. 2018;9(42):26834-26851.
Ishida, S., Akiyama, H., Umezawa, Y., Okada, K., Nogami, A., Oshikawa, G., ... Miura, O. (2018). Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2. Oncotarget, 9(42), pp. 26834-26851. doi:10.18632/oncotarget.25515.
Ishida S, et al. Mechanisms for mTORC1 Activation and Synergistic Induction of Apoptosis By Ruxolitinib and BH3 Mimetics or Autophagy Inhibitors in JAK2-V617F-expressing Leukemic Cells Including Newly Established PVTL-2. Oncotarget. 2018 Jun 1;9(42):26834-26851. PubMed PMID: 29928488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2. AU - Ishida,Shinya, AU - Akiyama,Hiroki, AU - Umezawa,Yoshihiro, AU - Okada,Keigo, AU - Nogami,Ayako, AU - Oshikawa,Gaku, AU - Nagao,Toshikage, AU - Miura,Osamu, Y1 - 2018/06/01/ PY - 2017/11/09/received PY - 2018/05/13/accepted PY - 2018/6/22/entrez PY - 2018/6/22/pubmed PY - 2018/6/22/medline KW - BH3 mimetic KW - JAK2-V617F KW - MPN KW - apoptosis KW - mTOR SP - 26834 EP - 26851 JF - Oncotarget JO - Oncotarget VL - 9 IS - 42 N2 - The activated JAK2-V617F mutant is very frequently found in myeloproliferative neoplasms (MPNs), and its inhibitor ruxolitinib has been in clinical use, albeit with limited efficacies. Here, we examine the signaling mechanisms from JAK2-V617F and responses to ruxolitinib in JAK2-V617F-positive leukemic cell lines, including PVTL-2, newly established from a patient with post-MPN secondary acute myeloid leukemia, and the widely used model cell line HEL. We have found that ruxolitinib downregulated the mTORC1/S6K/4EBP1 pathway at least partly through inhibition of the STAT5/Pim-2 pathway with concomitant downregulation of c-Myc, MCL-1, and BCL-xL as well as induction of autophagy in these cells. Ruxolitinib very efficiently inhibited proliferation but only modestly induced apoptosis. However, inhibition of BCL-xL/BCL-2 by the BH3 mimetics ABT-737 and navitoclax or BCL-xL by A-1331852 induced caspase-dependent apoptosis involving activation of Bak and Bax synergistically with ruxolitinib in HEL cells. On the other hand, the putative pan-BH3 mimetic obatoclax as well as chloroquine and bafilomycin A1 inhibited autophagy at its late stage and induced apoptosis in PVTL-2 cells synergistically with ruxolitinib. The present study suggests that autophagy as well as the anti-apoptotic BCL-2 family members, regulated at least partly by the mTORC1 pathway downstream of STAT5/Pim-2, protects JAK2-V617F-positive leukemic cells from ruxolitinib-induced apoptosis depending on cell types and may contribute to development of new strategies against JAK2-V617F-positive neoplasms. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/29928488/Mechanisms_for_mTORC1_activation_and_synergistic_induction_of_apoptosis_by_ruxolitinib_and_BH3_mimetics_or_autophagy_inhibitors_in_JAK2_V617F_expressing_leukemic_cells_including_newly_established_PVTL_2_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=25515 DB - PRIME DP - Unbound Medicine ER -