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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 244-259 |
| Number of pages | 16 |
| Journal | Blood |
| Volume | 141 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 19 2023 |
Funding
Y.L. was supported by National Institutes of Health ( R01 HL150624 , R56 DK119524 , R56 AG052501) , Department of Defense ( DoDW81XWH-18-1-0265 , DoD W81XWH-19-1-0575 ), the Leukemia & Lymphoma Society Translational Research Program award 6581-20 and the St. Baldrick’s Foundation Scholar Award. Y.B. and Z.-Y.Z. were supported by National Institutes of Health ( R01 CA069202 ) and the Robert C. and Charlotte Anderson Chair Endowment . S.B. was supported by a National Institutes of Health F31 Award ( F31HL160120 ). H.C. was supported by Natural Science Foundation of Chongqing ( cstc2020jcyj-msxmX0969 ). The authors thank Flow Cytometry Facility, Molecular and Translational Imaging Core Facility, Pathology Core Facility, Quantitative Data Sciences Core Facility, and Center for Comparative Medicine at the Northwestern University and Robert H. Lurie Comprehensive Cancer Center. The authors also acknowledge the Flow Cytometry Core and In vivo Therapeutic Core Laboratories at the Indiana University, which were sponsored, in part, by the National Institute of Diabetes and Digestive and Kidney Diseases Cooperative Center of Excellence in Hematology (CCEH) grant U54 DK106846. Y.L. was supported by National Institutes of Health (R01 HL150624, R56 DK119524, R56 AG052501), Department of Defense (DoDW81XWH-18-1-0265, DoD W81XWH-19-1-0575), the Leukemia & Lymphoma Society Translational Research Program award 6581-20 and the St. Baldrick's Foundation Scholar Award. Y.B. and Z.-Y.Z. were supported by National Institutes of Health (R01 CA069202) and the Robert C. and Charlotte Anderson Chair Endowment. S.B. was supported by a National Institutes of Health F31 Award (F31HL160120). H.C. was supported by Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0969). Contribution: H.C. Y.B. M.K. Z.-Y.Z. and Y.L. were responsible for the conception and/or design of the research; H.C. Y.B. M.K. S.X. W.C. S.B. S.C. J.M. F.N.M. S.V. J.P.R. J.W. Y.J. H.L. P.J. Z.-Y.Z. and Y.L. were involved in acquisition, analysis, or interpretation of data; J.M.C. H.S.B. L.S.L. J.K.A. E.A.E. W.T. H.B. D.T.H. and L.C.P. provided reagents and constructive advice to the study; H.C. Y.B. Z.-Y.Z. and Y.L. wrote the manuscript; and all authors read, commented on, and approved the manuscript. The authors would like to thank Flow Cytometry Facility, Molecular and Translational Imaging Core Facility, Pathology Core Facility, Quantitative Data Sciences Core Facility, and Center for Comparative Medicine at the Northwestern University and Robert H. Lurie Comprehensive Cancer Center. The authors also would like to acknowledge the Flow Cytometry Core and In vivo Therapeutic Core Laboratories at the Indiana University, which were sponsored, in part, by the NIDDK Cooperative Center of Excellence in Hematology (CCEH) grant U54 DK106846.
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology
