Home
Resources
Publications
Inhibition of USP9X Induces Apoptosis in FLT3-ITD-positive AML Cells Cooperatively by Inhibiting the Mutant Kinase Through Aggresomal Translocation and Inducing Oxidative Stress

Inhibition of USP9X Induces Apoptosis in FLT3-ITD-positive AML Cells Cooperatively by Inhibiting the Mutant Kinase Through Aggresomal Translocation and Inducing Oxidative Stress

Hiroki Akiyama, Yoshihiro Umezawa, Shinya Ishida, Keigo Okada, Ayako Nogami, Osamu Miura

Cancer Lett. 2019 Jul 1;453:84-94.

PMID: 30946869

Abstract:

FLT3-ITD and FLT3-TKD are the most frequent mutations in acute myeloid leukemia (AML) with the former associated with a poor prognosis. Here we show that inhibition of the deubiquitinase USP9X by its inhibitor WP1130 or EOAI3402143 (G9) induces apoptosis preferentially in cells transformed by these mutant kinases, including FLT3-ITD-positive AML cell line MV4-11 and primary AML cells. Mechanistically, WP1130 induced aggresomal translocation of the mutant kinases, particularly FLT3-ITD in its activated and autophosphorylated conformation, to block the downstream signaling events, which was aggravated by knock down of USP9X. Moreover, USP9X physically associated with FLT3-ITD to inhibit its K63-linked polyubiquitination, while FLT3-ITD induced tyrosine phosphorylation and degradation of USP9X through the ubiquitin/proteasome pathway. WP1130 or G9 also induced oxidative stress to stimulate stress-related MAP kinase pathways and DNA damage responses to activate in cooperation with inhibition of FLT3-ITD signaling the intrinsic mitochondria-mediated apoptotic pathway, which was synergistically enhanced by BH3 mimetics and prevented by overexpression of Bcl-xL or Mcl-1. Thus, USP9X represents a promising target for novel therapies against therapy-resistant FLT3-ITD-positive AML.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42410931	WP1130			Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: