Acute myeloid leukemia (AMI) is a lethal disease which dramatically increases in incidence in the aging population. Unfortunately, elderly patients afflicted with AML fare much worse than younger patients because of co-morbidities such as chronic heart disease, lung disease, and diabetes and, thus, the inability to tolerate the harsh treatments needed to cure AML. One of the most commonly mutated genes in AML is FMS-like Tyrosine Kinase Receptor (Flt3). Internal tandem duplications (ITD), an in-frame duplication of several amino acid residues in or near the juxtamembrane domain, in Flt3 are seen in nearly 25% of all AML patients and contribute to a poor prognosis;however, the molecular mechanisms contributing to mutant Flt3-induced leukemogenesis have yet to be elucidated. Tyrosine 599 (Y599) on WT-Flt3 has been shown to recruit the protein tyrosine phosphatase, Shp2, upon Flt3 ligand (FL) stimulation and normally activates the mitogen activated protein kinase, Erk. In a specific Flt3-ITD called N51-Flt3, Y599 is duplicated and leads to constitutive activation of Erk and STAT5. Based on these findings, we hypothesize that increased Shp2 recruitment to N51-Flt3 contributes to the transforming capacity of N51-Flt3 mutants. As a corollary, we hypothesize that the increased recruitment of Shp2 to Y599 plays a positive role in N51-Flt3-induced constitutive activation of Erk and STAT5. To examine this hypothesis we will Aim 1: (A) modify N51-Flt3 Y599 to phenylalanine (Y599F) in the first, the second, or both Y599 sites and utilize Baf3 cells to create stable cell lines;and (B) co-transduce murine hematopoietic progenitors with N51-Flt3 plus WT Shp2, Shp2C463A (phosphatase dead mutant), Shp2R32K (N-SH2 domain mutant), or Shp2R138K (C-SH2 domain mutant) and Aim 2: (A) transplant lethally irradiated mice with WT cells transduced with the previously described modified N51-Flt3 mutant constructs;and (B) transplant lethally irradiated mice with WT or Shp2-/- cells transduced with pMIEG3,WT-FLT3 or N51-Flt3. Results from these studies will provide the molecular basis of developing novel, molecularly-targeted, and less toxic therapies for AML, which is imperative for improved therapies in the elderly. LAYMAN'S DESCRIPTION: Acute myeloid leukemia is a common, but unfortunately incurable, blood cancer in the elderly population. Our laboratory has outlined studies to examine what induces the blood cells to become malignant with the long term goal of developing less toxic and curative drugs for this disease.
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