Journal Article

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

Müller, Jörg P., Heidel, Florian H., König, Rainer, Jacobsen, Ilse D., Hofbauer, Lorenz C., Ast, Volker, Figge, Marc Thilo, Svensson, Carl-Magnus, Böhmer, Frank- D., Hoffmann, Bianca, Kresinsky, Anne, Schnöder, Tina M., Hilger, Ingrid, Rauner, Martina

2019

Overview

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

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/39 / 59 / 59/57 / 631/67 / 631/67/1990/283/1897 / 64/60 / 82/29 / 96/31 / 96/34 / 96/95 / Acute myeloid leukemia / Anemia / Animals / Apoptosis / Bone and Bones / Bone Development - genetics / Bone growth / Bone remodeling / Bone Remodeling - genetics / CD45 antigen / Cell Biology / Cell Transformation, Neoplastic / Cells, Cultured / Choristoma - genetics / Choristoma - metabolism / Computed tomography / Cortical bone / Embryo, Mammalian / Female / Flt3 protein / fms-Like Tyrosine Kinase 3 - genetics / Genetic transformation / Genotype & phenotype / Human Genetics / Humans / Internal Medicine / Kinases / Leukemia, Myeloid, Acute - complications / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Leukocyte Common Antigens - deficiency / Leukocyte Common Antigens - genetics / Lymphocytes B / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mice, Transgenic / Monocytosis / Mutation / Myeloproliferative Disorders - complications / Myeloproliferative Disorders - genetics / Myeloproliferative Disorders - pathology / Nucleotide sequence / Oncology / Ossification (ectopic) / Osteogenesis / Osteogenesis - genetics / Osteoporosis / Osteoporosis - genetics / Osteoporosis - metabolism / Osteoporosis - pathology / Phenotype / Phenotypes / Porosity / Progenitor cells / Prognosis / Protein-tyrosine kinase receptors / Protein-tyrosine-phosphatase / Spleen / Stat5 protein / Stem cells / Tandem Repeat Sequences - genetics