This dissertation presents novel evidence that PTPN11 is activated by an upstream kinase, TNK2.
PTPN11-mutant JMML and AML primary patient cells have displayed significant sensitivity to TNK2
inhibition by dasatinib. My research has revealed that PTPN11 and TNK2 interact directly, allowing
for TNK2-dependent phosphorylation of PTPN11. There is a subsequent PTPN11-dependent
dephosphorylation of TNK2, suggesting a tightly coupled regulatory signaling loop. Consequent to
increased PTPN11 phosphorylation, co-expression of TNK2 and mutant PTPN11 synergistically increases
MAP kinase proliferative signaling and mouse bone marrow colony formation.
These increases can be significantly blocked with chemical inhibition of TNK2. Clinically, a
patient with recurrent JMML who was treated with
dasatinib had a therapeutic response. Collectively, these data indicate TNK2
as a promising target for PTPN11-mutant cancers.