© Universitätsklinikum Freiburg
Micrograph showing JMML
New research suggests dasatinib could treat certain patients with juvenile myelomonocytic leukemia (JMML) or acute myeloid leukemia (AML).
The study showed that TNK2 inhibition has a negative effect on PTPN11-mutant leukemias.
PTPN11-mutant JMML and AML cells were sensitive to treatment with dasatinib, which inhibits TNK2.
Dasatinib also induced hematologic remission in a patient with PTPN11-mutant JMML.
Investigators reported these results in Science Signaling.
Past research showed that mutations in PTPN11 result in excessive cell proliferation and drive tumor growth in some cases of JMML and AML.
In the current study, investigators analyzed PTPN11-mutated leukemia cells and found that PTPN11 is activated by TNK2.
The investigators said TNK2 phosphorylates PTPN11, which then dephosphorylates TNK2 in a negative feedback loop. They also found that coexpression of TNK2 and mutant PTPN11 results in “robust” MAPK pathway activation.
Inhibiting TNK2 with dasatinib blocked MAPK signaling and colony formation in vitro.
Additional experiments showed that PTPN11-mutant AML samples were significantly more sensitive to dasatinib than wild-type AML samples.
Investigators also tested dasatinib in a sample from a JMML patient carrying a PTPN11 G60R mutation.
This patient’s cells were 10 times more sensitive to dasatinib than the average sample from a cohort of 151 patients who had AML, acute lymphoblastic leukemia, myeloproliferative neoplasms, or chronic lymphocytic leukemia.
Because the JMML patient’s cells were so responsive to dasatinib, the investigators decided to administer the drug to the patient.
The patient achieved sustained hematologic remission with dasatinib, and this allowed him to receive a stem cell transplant using an unrelated cord blood donor. The patient had previously failed 2 transplants (with myeloablative conditioning) from a matched sibling donor.
The third transplant prolonged the patient’s life by a year, but he eventually died of relapsed disease.
The investigators said this case study and the in vitro results support further investigation into the efficacy of dasatinib and other TNK2 inhibitors in PTPN11-mutant leukemias.