TY - JOUR
T1 - PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371
AU - Chen, Hongxia
AU - Bai, Yunpeng
AU - Kobayashi, Michihiro
AU - Xiao, Shiyu
AU - Cai, Wenjie
AU - Barajas, Sergio
AU - Chen, Sisi
AU - Miao, Jinmin
AU - Meke, Frederick Nguele
AU - Vemula, Sasidhar
AU - Ropa, James P.
AU - Croop, James M.
AU - Boswell, H. Scott
AU - Wan, Jun
AU - Jia, Yuzhi
AU - Liu, Huiping
AU - Li, Loretta S.
AU - Altman, Jessica K.
AU - Eklund, Elizabeth A.
AU - Ji, Peng
AU - Tong, Wei
AU - Band, Hamid
AU - Huang, Danny T.
AU - Platanias, Leonidas C.
AU - Zhang, Zhong Yin
AU - Liu, Yan
N1 - Publisher Copyright:
© 2023 The American Society of Hematology
PY - 2023/1/19
Y1 - 2023/1/19
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2022016580
DO - 10.1182/blood.2022016580
M3 - Article
C2 - 36206490
AN - SCOPUS:85143881888
SN - 0006-4971
VL - 141
SP - 244
EP - 259
JO - Blood
JF - Blood
IS - 3
ER -