Lack of CD45 in FLT3-ITD mice results in a myeloproliferative phenotype, cortical porosity, and ectopic bone formation.

Kresinsky A, Schnöder TM, Jacobsen ID, Rauner M, Hofbauer LC, Ast V, König R, Hoffmann B, Svensson CM, Figge MT, Hilger I, Heidel FH, Böhmer FD, Müller JP (2019) Lack of CD45 in FLT3-ITD mice results in a myeloproliferative phenotype, cortical porosity, and ectopic bone formation. Oncogene 38(24), 4773-4787. PubMed

Abstract

The receptor-tyrosine kinase FLT3 is expressed in myeloid and lymphoid progenitor cells. Activating mutations in FLT3 occur in 25 – 30 % of acute myeloid leukaemia (AML) patients. Most common are internal tandem duplications of sequence (ITD) leading to constitutive FLT3- ITD kinase activity with altered signalling quality promoting leukaemic cell transformation. Recently we observed an attenuating role of the receptor-like protein-tyrosine phosphatase (RPTP) CD45/Ptprc for FLT3 signalling in vitro. Low level expression of this abundant RPTP correlates with poor prognosis of FLT3-ITD positive AML patients. To get further insight into the regulatory role of Ptprc for FLT3-ITD activity in vivo, Ptprc knock-out mice were bred with FLT3-ITD knock-in mice. Inactivation of the Ptprc gene in FLT3-ITD mice resulted in drastically shortened life-span and development of severe monocytosis, a block in B cell development and anaemia. The myeloproliferative phenotype was associated with extramedullary haematopoiesis, splenohepatomegaly and severe alterations of organ structures. The phenotypic alterations were associated with increased transforming signalling of FLT3-ITD including activation of its downstream target STAT5. These data reveal the capacity of Ptprc for regulation of FLT3-ITD signalling 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. In spleen ectopic bone formation was observed. The observed bone phenotypes suggest a previously unappreciated capacity of FLT3-ITD (and presumably FLT3) to regulate bone development/remodelling, which is under negative control of CD45/Ptprc.

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doi: 10.1038/s41388-019-0757-y PMID: 30820040