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Sci Signal. 2018 Jul 17;11(539). pii: eaao5617. doi: 10.1126/scisignal.aao5617.

Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia.

Author information

1
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA.
2
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
3
Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA.
4
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
5
Oregon Clinical and Translational Research Institute, Portland, OR 97239, USA.
6
Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA.
7
Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.
8
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. changb@ohsu.edu tynerj@ohsu.edu.
9
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA. changb@ohsu.edu tynerj@ohsu.edu.

Abstract

The protein tyrosine phosphatase PTPN11 is implicated in the pathogenesis of juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and other malignancies. Activating mutations in PTPN11 increase downstream proliferative signaling and cell survival. We investigated the signaling upstream of PTPN11 in JMML and AML cells and found that PTPN11 was activated by the nonreceptor tyrosine/serine/threonine kinase TNK2 and that PTPN11-mutant JMML and AML cells were sensitive to TNK2 inhibition. In cultured human cell-based assays, PTPN11 and TNK2 interacted directly, enabling TNK2 to phosphorylate PTPN11, which subsequently dephosphorylated TNK2 in a negative feedback loop. Mutations in PTPN11 did not affect this physical interaction but increased the basal activity of PTPN11 such that TNK2-mediated activation was additive. Consequently, coexpression of TNK2 and mutant PTPN11 synergistically increased mitogen-activated protein kinase (MAPK) signaling and enhanced colony formation in bone marrow cells from mice. Chemical inhibition of TNK2 blocked MAPK signaling and colony formation in vitro and decreased disease burden in a patient with PTPN11-mutant JMML who was treated with the multikinase (including TNK2) inhibitor dasatinib. Together, these data suggest that TNK2 is a promising therapeutic target for PTPN11-mutant leukemias.

PMID:
30018082
PMCID:
PMC6168748
DOI:
10.1126/scisignal.aao5617
[Indexed for MEDLINE]
Free PMC Article

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