PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371
Year: 2022
Type: article
Abstract: Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, 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-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, 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.
Source: Blood
Authors: Hongxia Chen, Yunpeng Bai, Michihiro Kobayashi, Shiyu Xiao, Wenjie Cai, Sergio Barajas, Sisi Chen, Jinmin Miao, Frederick Nguele Meke, Sasidhar Vemula, James P. Ropa, James M. Croop, H. Scott Boswell, Jun Wan, Yuzhi Jia, Huiping Liu, Loretta S. Li, Jessica K. Altman, Elizabeth A. Eklund, Peng Ji, Wei Tong, Hamid Band, Danny T. Huang, Leonidas C. Platanias, Zhong-Yin Zhang, Yan Liu
Institutions: Northwestern University, Chongqing University, Purdue University West Lafayette, Center for Cancer Research, Indiana University Indianapolis, Indiana University School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Jesse Brown VA Medical Center, Children's Hospital of Philadelphia, University of Pennsylvania, University of Nebraska Medical Center, Cancer Research UK Scotland Institute, University of Glasgow
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, Northwestern University, Natural Science Foundation of Chongqing, National Institutes of Health, Robert H. Lurie Comprehensive Cancer Center, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G1699259716, G1790519008, TARGETING LEUKEMIA-INITIATING CELLS TO IMPROVE LEUKEMIA TREATMENT, G2957078104, G3807550013, G4119534169, G4571580823, Northwestern University Clinical and Translational Science Institute (NUCATS), G581773441, G5850682332, G6582274034, G695691055, Regulation of Ribosome Biogenesis in Hematopoietic Stem Cells, G8167257546, Molecular mechanisms underlying clonal expansion of hematopoietic stem cells, G844697008, G9000160688, G9000304140, Novel Regulation of Oncogenic NRAS Signaling in Myeloid Malignancies, Structure/Function of Protein Tyrosine Phosphatases, Autophagy, Inflammation and Metabolism (AIM) in Disease Center - Phase 2.
OpenAlex ID: W4303456975