Molecular Mechanisms of FLT3-ITD-Induced Leukemogenesis
dc.contributor.advisor | Chan, Rebecca, J. | |
dc.contributor.author | Nabinger, Sarah Cassidy | |
dc.contributor.other | Cornetta, Kenneth G. | |
dc.contributor.other | Morral, Nuria | |
dc.contributor.other | Kapur, Reuben | |
dc.date.accessioned | 2012-08-07T14:43:42Z | |
dc.date.available | 2012-08-07T14:43:42Z | |
dc.date.issued | 2012-08-07 | |
dc.degree.date | 2012 | en_US |
dc.degree.discipline | Department of Medical & Molecular Genetics | en |
dc.degree.grantor | Indiana University | en_US |
dc.degree.level | Ph.D. | en_US |
dc.description | Indiana University-Purdue University Indianapolis (IUPUI) | en_US |
dc.description.abstract | Internal tandem duplications in FMS-like receptor tyrosine kinase (FLT3-ITDs) are seen in approximately 25% of all acute myeloid leukemia (AML) patients. FLT3-ITDs induce FLT3 ligand (FL)-independent cellular hyperproliferation, promiscuous and aberrant activation of STAT5, and confer a poor prognosis in patients; however, the molecular mechanisms contributing to FLT3-ITD-induced malignancy remain largely unknown. The protein tyrosine phosphatase, Shp2, is important for normal hematopoiesis as well as hematopoietic stem cell (HSC) differentiation, engraftment, and self-renewal. Furthermore, FLT3-ITD- or constitutive active STAT5-expressing CD34+ cells demonstrate enhanced hematopoietic stem cell self-renewal. Together with the previous findings that Shp2 is critical for normal hematopoiesis, that dysregulated Shp2 function contributes to myeloid malignancies, and that Shp2 has been shown to interact with WT-FLT3 tyrosine 599, which is commonly duplicated in FLT3-ITDs, a positive role for Shp2 in FLT3-ITD-induced signaling and leukemogenesis is implied. I demonstrated that Shp2 is constitutively associated with the reported FLT3-ITDs, N51-FLT3 and N73-FLT3, compared to WT-FLT3; therefore, I hypothesized that increased Shp2 recruitment to N51-FLT3 or N73-FLT3 contributes to hyperproliferation and hyperactivation of STAT5. I also hypothesized that Shp2 cooperates with STAT5 to activate STAT5 transcriptional targets contributing to the up-regulation of pro-leukemic proteins. Finally, I hypothesized that reduction of Shp2 would result in diminished N51-FLT3-induced hyperproliferation and activation of STAT5 in vitro, and prevent FLT3-ITD-induced malignancy in vivo. I found that genetic disruption of Ptpn11, the gene encoding Shp2, or pharmacologic inhibition of Shp2 with the novel Shp2 inhibitor, II-B08, resulted in significantly reduced FLT3-ITD-induced hematopoietic cell hyperproliferation and STAT5 hyperphosphorylation. I also demonstrated a novel role of Shp2 in the nucleus of FLT3-ITD-expressing hematopoietic cells where Shp2 and STAT5 co-localized at the promoter region of STAT5-transcriptional target and pro-survival protein, Bcl-XL. Furthermore, using a Shp2flox/flox;Mx1Cre+ mouse model, I demonstrated that reduced Shp2 expression in hematopoietic cells resulted in an increased latency to and reduced severity of FLT3-ITD-induced malignancy. Collectively, these findings demonstrate that Shp2 plays an integral role in FLT3-ITD-induced malignancy and suggest that targeting Shp2 may be a future therapeutic option for treating FLT3-ITD-positive AML patients. | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/2883 | |
dc.identifier.uri | http://dx.doi.org/10.7912/C2/1948 | |
dc.language.iso | en_US | en_US |
dc.subject | FLT3, FLT3-ITD, Shp2, STAT5, Acute Myeloid Leukemia | en_US |
dc.subject.lcsh | Acute myeloid leukemia | en_US |
dc.subject.lcsh | Blood -- Diseases | en_US |
dc.subject.lcsh | Protein-tyrosine kinase | en_US |
dc.subject.lcsh | Cancer -- Research | en_US |
dc.subject.lcsh | Hematopoiesis | en_US |
dc.subject.lcsh | Hematopoietic stem cells | en_US |
dc.title | Molecular Mechanisms of FLT3-ITD-Induced Leukemogenesis | en_US |
dc.type | Thesis | en |