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Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells.
Cancers (Basel). 2020 Feb 10; 12(2)C

Abstract

JAK2-V617F plays a key role in the pathogenesis of myeloproliferative neoplasm. However, its inhibitor ruxolitinib has shown limited clinical efficacies because of the ruxolitinib-persistent proliferation of JAK2-V617F-positive cells. We here demonstrate that the USP9X inhibitor WP1130 or EOAI3402143 (G9) inhibited proliferation and induced apoptosis more efficiently in cells dependent on JAK2-V617F than on cytokine-activated JAK2. WP1130 preferentially downregulated activated and autophosphorylated JAK2-V617F by enhancing its K63-linked polyubiquitination and inducing its aggresomal translocation to block downstream signaling. Furthermore, JAK2-V617F associated physically with USP9X in leukemic HEL cells. Induction of apoptosis by inhibition of USP9X was mediated through the intrinsic mitochondria-mediated pathway, synergistically enhanced by BH3 mimetics, prevented by overexpression of Bcl-xL, and required oxidative stress to activate stress-related MAP kinases p38 and JNK as well as DNA damage responses in HEL cells. Although autophosphorylated JAK2-V617F was resistant to WP1130 in the ruxolitinib-persistent HEL-R cells, these cells expressed Bcl-2 and Bcl-xL at lower levels and showed an increased sensitivity to WP1130 as well as BH3 mimetics as compared with ruxolitinib-naive HEL cells. Thus, USP9X represents a promising target along with anti-apoptotic Bcl-2 family members for novel therapeutic strategies against JAK2-V617F-positive myeloproliferative neoplasms, particularly under the ruxolitinib persistence conditions.

Authors+Show Affiliations

Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. Department of Clinical Laboratory, Medical Hospital, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8519, Japan.Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32050632

Citation

Akiyama, Hiroki, et al. "Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically With BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells." Cancers, vol. 12, no. 2, 2020.
Akiyama H, Umezawa Y, Watanabe D, et al. Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells. Cancers (Basel). 2020;12(2).
Akiyama, H., Umezawa, Y., Watanabe, D., Okada, K., Ishida, S., Nogami, A., & Miura, O. (2020). Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells. Cancers, 12(2). https://doi.org/10.3390/cancers12020406
Akiyama H, et al. Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically With BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells. Cancers (Basel). 2020 Feb 10;12(2) PubMed PMID: 32050632.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells. AU - Akiyama,Hiroki, AU - Umezawa,Yoshihiro, AU - Watanabe,Daisuke, AU - Okada,Keigo, AU - Ishida,Shinya, AU - Nogami,Ayako, AU - Miura,Osamu, Y1 - 2020/02/10/ PY - 2020/01/08/received PY - 2020/01/29/revised PY - 2020/02/06/accepted PY - 2020/2/14/entrez PY - 2020/2/14/pubmed PY - 2020/2/14/medline KW - BH3 mimetics KW - JAK2-V617F KW - USP9X KW - WP1130 KW - myeloproliferative neoplasms KW - oxidative stress KW - ruxolitinib JF - Cancers JO - Cancers (Basel) VL - 12 IS - 2 N2 - JAK2-V617F plays a key role in the pathogenesis of myeloproliferative neoplasm. However, its inhibitor ruxolitinib has shown limited clinical efficacies because of the ruxolitinib-persistent proliferation of JAK2-V617F-positive cells. We here demonstrate that the USP9X inhibitor WP1130 or EOAI3402143 (G9) inhibited proliferation and induced apoptosis more efficiently in cells dependent on JAK2-V617F than on cytokine-activated JAK2. WP1130 preferentially downregulated activated and autophosphorylated JAK2-V617F by enhancing its K63-linked polyubiquitination and inducing its aggresomal translocation to block downstream signaling. Furthermore, JAK2-V617F associated physically with USP9X in leukemic HEL cells. Induction of apoptosis by inhibition of USP9X was mediated through the intrinsic mitochondria-mediated pathway, synergistically enhanced by BH3 mimetics, prevented by overexpression of Bcl-xL, and required oxidative stress to activate stress-related MAP kinases p38 and JNK as well as DNA damage responses in HEL cells. Although autophosphorylated JAK2-V617F was resistant to WP1130 in the ruxolitinib-persistent HEL-R cells, these cells expressed Bcl-2 and Bcl-xL at lower levels and showed an increased sensitivity to WP1130 as well as BH3 mimetics as compared with ruxolitinib-naive HEL cells. Thus, USP9X represents a promising target along with anti-apoptotic Bcl-2 family members for novel therapeutic strategies against JAK2-V617F-positive myeloproliferative neoplasms, particularly under the ruxolitinib persistence conditions. SN - 2072-6694 UR - https://www.unboundmedicine.com/medline/citation/32050632/Inhibition_of_USP9X_Downregulates_JAK2_V617F_and_Induces_Apoptosis_Synergistically_with_BH3_Mimetics_Preferentially_in_Ruxolitinib_Persistent_JAK2_V617F_Positive_Leukemic_Cells_ L2 - http://www.mdpi.com/resolver?pii=cancers12020406 DB - PRIME DP - Unbound Medicine ER -
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