Indiana University-Purdue University Indianapolis (IUPUI) / Internal tandem duplications in the fms-like tyrosine kinase receptor (FLT3-ITDs) cause constitutive activation of the receptor and confer a poor prognosis in acute myeloid leukemia (AML). We hypothesized that Shp2 interacts with FLT3-ITD via protein complexes at tyrosine (Y) 768, 955, and/or 969 and that Shp2 and PI3K work cooperatively to promote FLT3-ITD-induced leukemogenesis. Consistently, mutation of N51-FLT3 tyrosine 768 to phenylalanine reduced proliferation and levels of phospho-Erk compared to N51-FLT3-expressing cells while having no effect on levels of phospho-STAT5. In transplants, C3H/HeJ mice injected with either WT-FLT3-, N51-FLT3-, or N51-Y768F-expressing cells showed that mutation of Y768 had no effect on overall survival. In addition, pharmacologic inhibition of Shp2 with II-B08 or PI3K with GDC-0941 in N51-FLT3-expressing cells and primary patient samples showed decreased proliferation. A possible mechanistic explanation for reduced proliferation and selective reduction of P-Erk levels in the N51-FLT3-Y768-expressing cells is through decreased recruitment of Grb2, which participates with son of sevenless, SOS, to activate the RAS-Erk signaling pathway. The lack of improvement in overall survival could be due to preserved STAT5 signaling, as observed during in vitro experiments. Collectively, these data suggest that the tyrosine 768 residue plays an important role in phospho-Erk signaling in N51-FLT3-expressing cells, and that pharmacologic therapy with Shp2 or PI3K inhibitors may provide a novel treatment approach for FLT3-ITD positive AML. For future directions, we plan to treat mice with the Shp2 inhibitor, II-B08, the PI3K inhibitor, GDC-0941, or a combination to determine the effect on overall survival.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10901 |
| Date | 07 1900 |
| Creators | Bowling, Joshua D. |
| Contributors | Chan, Rebecca J., Paczesny, Sophie, Ferguson, Michael James |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
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