Tag: Bill Chang

PTPN11 S502P and Tyrosine Kinase Non-Receptor-2 increase RAS/MAPK signaling in Acute Myeloid Leukemia

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.

Effects of Alisertib in Acute Lymphoblastic Leukemia NSG Mouse Models

Presenter(s): Corinne Togiai

Faculty Mentor(s): Bill Chang

Oral Session 3 M

Acute Lymphoblastic Leukemia (ALL) is a common cause for disease-related mortality in children and adolescents. As we have made great strides in curing ALL we have identified subsets of diseases that continue to have a poor prognosis. To develop novel targeted therapies in hopes to advance the treatment of these diseases, our lab initiated the use of rapid, state-of-the-art genetic and functional assays to identify aberrant activated pathways from primary patient leukemic samples. Results through collaborative research with the Knight Cancer Institute Leukemia Research Group, have identified significant hypersensitivity to different cellular pathway inhibition. Our current proposal builds on these findings. We have identified a unique hypersensitivity of certain subsets of leukemic cells to inhibition of the Aurora class of cell cycle kinases. Aurora kinases are members of serine/threonine kinases that play pivotal roles for the cell to faithfully undergo mitosis. Studies have shown that certain cancers are heavily dependent on the activity of these kinases beyond mitosis and that these kinases can be targeted by specific small molecule drugs. Our preliminary data is the first to identify subsets of ALL that are hypersensitive to aurora kinase inhibition. What remains unknown is the mechanism of hypersensitivity in subsets of ALL as well as in vivo validation.

Other future directions in parallel aim towards determining the mechanism of hypersensitivity to Aurora kinase inhibitors in subsets of ALL, and developing in vivo models testing single agent and combination therapy specifically targeting these pathways.