In this section

PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371

Chen, H. et al. (2023) PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371. Blood Vessels, 141(3), pp. 244-259. (doi: 10.1182/blood.2022016580) (PMID:36206490)

[img] Text
282270.pdf - Accepted Version
3MB

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FLT3 is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. While protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared to normal human hematopoietic stem and progenitor cells (HSPCs), the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-ITD-driven leukemia and extend the survival of leukemic mice. Further, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Huang, Professor Danny
Authors: Chen, H., Bai, Y., Kobayashi, M., Xiao, S., Cai, W., Barajas, S., Chen, S., Miao, J., Meke, F. N., Vemula, S., Ropa, J. P., Croop, J. M., Boswell, H. S., Wan, J., Jia, Y., Liu, H., Li, L. S., Altman, J. K., Eklund, E. A., Ji, P., Tong, W., Band, H., Huang, D. T., Platanias, L. C., Zhang, Z.-Y., and Liu, Y.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Blood Vessels
Publisher:S. Karger AG
ISSN:1018-1172
ISSN (Online):1528-0020
Published Online:11 October 2022
Copyright Holders:Copyright © 2023 by The American Society of Hematology
First Published:First published in Blood 141(3):244-259
Publisher Policy:Reproduced in accordance with the publisher copyright policy
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Deposit and Record Details