Receptor protein-tyrosine phosphatases controlling activity of the oncoprotein FLT3 ITD

Kresinsky, Anne GND

The receptor tyrosine kinase FLT3 is expressed in myeloid and lymphoid progenitor cells. Activating mutations in FLT3 occur in 2530% of acute myeloid leukemia (AML) patients. Most common are internal tandem duplications of sequence (ITD) leading to constitutive FLT3-ITD kinase activity with an altered signaling quality promoting leukemic cell transformation. Here, the attenuating role of the receptor-like protein tyrosine phosphatases (RPTP) DEP1/Ptprj and CD45/Ptprc in FLT3 ITD signaling was observed in vitro. Furthermore, low level expression of either Ptprj or Ptprc correlates with a poor prognosis of FLT3 ITD-positive AML patients. To get a further insight into the regulatory role of Ptprj and Ptprc in FLT3 ITD activity in vivo, Ptprj or Ptprc knock-out mice were bred with FLT3 ITD knock-in mice. Inactivation of the Ptprj or Ptprc gene in FLT3 ITD mice resulted in a drastically shortened life span and development of severe monocytosis, a block in B-cell development and anemia. The myeloproliferative phenotype was associated with extramedullary hematopoiesis, splenohepatomegaly and severe alterations of organ structures. The phenotypic alterations were associated with increased transforming signaling of FLT3 ITD, including activation of its downstream target STAT5. These data reveal the capacity of Ptprj and Ptprc for the regulation of FLT3 ITD signaling activity in vivo. In addition, histopathology and computed tomography (CT) revealed an unexpected bone phenotype; the FLT3 ITD Ptprc-/- mice, but none of the controls, showed pronounced alterations in bone morphology and, in part, apparent features of osteoporosis. The observed bone phenotypes suggest a previously unappreciated capacity of FLT3 ITD (and presumably FLT3) to regulate bone development/remodeling, which is under negative control of CD45/Ptprc.

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Kresinsky, Anne: Receptor protein-tyrosine phosphatases controlling activity of the oncoprotein FLT3 ITD. Jena 2019.

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