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

Oncogene volume 38, pages 4773–4787 (2019)Cite this article

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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 an altered signalling quality promoting leukaemic cell transformation. Here, we observed the attenuating role of the receptor-like protein tyrosine phosphatase (RPTP) CD45/Ptprc in FLT3 signalling in vivo. Low level expression of this abundant RPTP correlates with a poor prognosis of FLT3-ITD-positive AML patients. To get a further insight into the regulatory role of Ptprc in 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 a 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 the 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 the 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.

Key points

  • Low PTPRC expression of FLT3-ITD-positive AML patients correlates with poor prognosis

  • FLT3-ITD/Ptprc-/- mice develop severe monocytosis, a block in B-cell formation and anaemia

  • FLT3-ITD/Ptprc-/- mice develop myeloproliferative neoplasm with extramedullary haematopoiesis and splenohepatomegaly

  • Inactivation of Ptprc in the presence of FLT3-ITD results in cortical porosity and ectopic bone formation

  • Ptprc is negatively regulating transforming FLT3-ITD signalling in vivo

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Acknowledgements

We are thankful to Jörg Cammenga (Lund University, Sweden) for kindly providing FLT3-ITD mice and Klaus Metzeler for providing array data. The work was supported by Deutsche Forschungsgemeinschaft (grant Mu955/11-1), the Federal Ministry of Education and Research (BMBF), Germany, CancerTel-Sys (FKZ 01ZX1302B, 01ZX1602B) and IFB/CSCC (01EO1002, 01EO1502).

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Authors and Affiliations

  1. Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Jena, Germany

    Anne Kresinsky, Frank- D. Böhmer & Jörg P. Müller

  2. Internal medicine II, Department of Haematology and Oncology, Jena University Hospital, Jena, Germany

    Tina M. Schnöder & Florian H. Heidel

  3. Research Group Microbial Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany

    Ilse D. Jacobsen

  4. Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany

    Martina Rauner & Lorenz C. Hofbauer

  5. Network modelling, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany

    Volker Ast & Rainer König

  6. Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany

    Volker Ast & Rainer König

  7. Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany

    Bianca Hoffmann, Carl-Magnus Svensson & Marc Thilo Figge

  8. Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany

    Marc Thilo Figge

  9. Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany

    Ingrid Hilger

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  1. Anne Kresinsky
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Contributions

AK, JPM performed the research; VA, RK processed bioinformatics; BH, CMS, MTF processed CT data; TMS, FH, FDB, JPM analysed and interpreted the data; IDJ, LH, FDB, FH, JPM designed and conceptualised the research; AK, MR, FDB, FH, JPM wrote the manuscript. All the authors read and approved the manuscript.

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Correspondence to Jörg P. Müller.

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Kresinsky, A., Schnöder, T.M., Jacobsen, I.D. et al. Lack of CD45 in FLT3-ITD mice results in a myeloproliferative phenotype, cortical porosity, and ectopic bone formation. Oncogene 38, 4773–4787 (2019). https://doi.org/10.1038/s41388-019-0757-y

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