Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia

Chelsea Jenkins, Samuel B. Luty, Julia Maxson, Christopher A. Eide, Melissa L. Abel, Corinne Togiai, Eneida Nemecek, Daniel Bottomly, Shannon McWeeney, Beth Wilmot, Marc Loriaux, Bill Chang, Jeffrey Tyner

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbereaao5617
JournalScience Signaling
Volume11
Issue number539
DOIs
StatePublished - Jul 17 2018

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Juvenile Myelomonocytic Leukemia
Leukemia
Acute Myeloid Leukemia
Myeloid Cells
Mitogen-Activated Protein Kinases
Cells
Mutation
Protein Tyrosine Phosphatases
Protein-Serine-Threonine Kinases
Bone Marrow Cells
Tyrosine
Assays
Cell Survival
Bone
Chemical activation
Feedback
Synthetic Lethal Mutations
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia. / Jenkins, Chelsea; Luty, Samuel B.; Maxson, Julia; Eide, Christopher A.; Abel, Melissa L.; Togiai, Corinne; Nemecek, Eneida; Bottomly, Daniel; McWeeney, Shannon; Wilmot, Beth; Loriaux, Marc; Chang, Bill; Tyner, Jeffrey.

In: Science Signaling, Vol. 11, No. 539, eaao5617, 17.07.2018.

Research output: Contribution to journalArticle

Jenkins C, Luty SB, Maxson J, Eide CA, Abel ML, Togiai C et al. Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia. Science Signaling. 2018 Jul 17;11(539). eaao5617. https://doi.org/10.1126/scisignal.aao5617
Jenkins, Chelsea ; Luty, Samuel B. ; Maxson, Julia ; Eide, Christopher A. ; Abel, Melissa L. ; Togiai, Corinne ; Nemecek, Eneida ; Bottomly, Daniel ; McWeeney, Shannon ; Wilmot, Beth ; Loriaux, Marc ; Chang, Bill ; Tyner, Jeffrey. / Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia. In: Science Signaling. 2018 ; Vol. 11, No. 539.
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