Presenter(s): Corinne Togiai − Biology
Faculty Mentor(s): Chelsea Jenkins, Dr. Bill Chang
Oral Session 3M
Research Area: Natural/Physical Science (Cancer Biology)
Funding: OHSU Knight Cancer Institute, Oregon Health and Science University, Howard Hughes Medical Institute, Druker Laboratory, Dr. Brian Druker, Dr. Bill Chang, Dr. Jeff Tyner and Dr. Chelsea Jenkins
PTPN11 is a gene which encodes the protein tyrosine phosphatase SHP2, an auto-inhibited protein that dephosphorylates targets in many of the proliferative pathways such as Ras/MAPK. This gene, PTPN11, is the driving force in 35% of Juvenile Myelomoncytic Leukemia (JMML) patients and 10% of Acute Myeloid Leukemia (AML) patients. Moreover, cells from a JMML patient were found to be sensitive to tyrosine kinase inhibitor dasatanib. This is thought due to interactions between PTPN11 and tyrosine non-kinase 2 (TNK2), which is a dasatanib target. Therefore, we hypothesized that HEK 293 T17 cells co-transfected with mutant PTPN11 S502P and TNK2 will display decreased phospho-TNK2 and increased phospho-ERK, as seen in the JMML mutant PTPN11 E76K. In my project, I worked with PTPN11 mutation identified in an AML patient sample (S502P) that has shown sensitivity to the drug Dasatanib, a kinase inhibitor that blocks the action of abnormal proteins that signal cells to proliferate, ultimately helping stop the spread of cancer cells. I performed multiple western blots consisting of: transfections, gel electrophoresis, and protein detection. Results show S502P mutant PTPN11 acts like E76K mutant in that it activates the RAS/MAPK pathway, and S502P mutant PTPN11 dephosphorylates TNK2. In conclusion, the patient sample S502P mutant has shown a dephosphorylating effect on TNK2 that has not been seen in any previous studies. Data suggests that this mutant also works with TNK2 to increase RAS/MAPK signaling. Through this interaction this mutation can be tested and targeted by Dasatinib to stop the proliferation of leukemic cells.