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

Author:

Chen Hongxia123,Bai Yunpeng4,Kobayashi Michihiro5,Xiao Shiyu2ORCID,Cai Wenjie25ORCID,Barajas Sergio25ORCID,Chen Sisi5,Miao Jinmin4,Meke Frederick Nguele4ORCID,Vemula Sasidhar5,Ropa James P.6,Croop James M.5,Boswell H. Scott7,Wan Jun8,Jia Yuzhi9,Liu Huiping910ORCID,Li Loretta S.1011,Altman Jessica K.210,Eklund Elizabeth A.21012,Ji Peng1013ORCID,Tong Wei14ORCID,Band Hamid15ORCID,Huang Danny T.16ORCID,Platanias Leonidas C.21012,Zhang Zhong-Yin4,Liu Yan210

Affiliation:

1. 1Department of Hematology and Oncology, Chongqing University Three Gorges Hospital, Chongqing, China

2. 2Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL

3. 3School of Medicine, Chongqing University, Chongqing, China

4. 4Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN

5. 5Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN

6. 6Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN

7. 7Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

8. 8Department of Medical Genetics, Indiana University, Indianapolis, IN

9. 9Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL

10. 10Robert H. Lurie Comprehensive Cancer Center, Chicago, IL

11. 11Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL

12. 12Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL

13. 13Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL

14. 14Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA

15. 15Department of Genetics, University of Nebraska Medical Center, Omaha, NB

16. 16Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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