Morphological changes in megakaryocytes during hydroxyurea treatment of polycythemia vera and primary myelofibrosis

Introduction. Myeloproliferative diseases are characterized by the disorder of one or more myelopoiesis cell lines in the bone marrow. In true polycythemia, primary myelofibrosis and essential thrombocythemia, hyperplasia of the megakaryocytic lineage occurs with the formation of their atypical forms. In megakaryocytes in these neoplasms, inhibition of apoptosis is observed, which contributes to the preservation of atypical forms. Hydroxyurea is used to treat Ph-negative mycloproliferative diseases. The mechanism of action of this drug is associated with the inhibition of ribonucleotide reductase. The aim of this study was to provide an ultrastructural characteristic of megakaryocytes with the definition of potential therapeutic targets in the treatment of Ph-negative MPN with hydroxyurea.
Materials and methods. Four bone marrow samples obtained from patients were examined using the iliac spine trephine biopsy method. The patients were diagnosed with true polycythemia and primary myelofibrosis. All the presented patients, regardless of the nosology, were treated with the drug - hydroxyurea in therapeutic doses.
Result. In bone marrow samples, in the cytoplasm of megakaryocytes, "voids" were visualized that looked like optically empty vacuoles. During electron microscopy of megakaryocytes, in bone marrow preparations, in the projections of the optically empty vacuoles described above, cavities from round to irregular in shape, of different sizes were determined. In some of these cavities, layered masses were visualized, the plates of which had a concentric direction - autophagic vacuoles. Layered structures, with concentrically directed plates, resembling the contents of autophagic vacuoles, were also determined outside the cells. Condensation of chromatin in the nuclei of megakaryocytes was not observed.
Conclusion. The results obtained in the study suggest that hydroxyurea initiates an autophagic response in megakaryocytes during treatment of Ph-negative myeloproliferative neoplasms. Possibly, as the initiation of autophagic cell death, which could explain its therapeutic effect. However, it is also possible that autophagy has a cytoprotective role. Thus, autophagy is a potential therapeutic target in treatment with hydroxyurea.

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