Hyaluronan in normal and malignant bone marrow a clinical and morphological study with emphasis on myelofibrosis

Abstract: Fibrosis in the bone marrow is usually denominated myelofibrosis and may contribute to impaired hematopoiesis. Myelofibrosis is seen both in malignant and non-malignant diseases.The normal microenvironment in the bone marrow consists of a heterogenous population of hematopoietic and non-hematopoietic stromal cells, their extracellular products and hematopoietic cytokines. The stromal cells produce a complex array of molecules, among others collagens and glycosaminoglycans (GAGs) of which hyaluronan (HYA) is the most abundant. Marrow fibrosis results from an increased deposition of collagens, which are polypeptides. Staining for reticulin, mostly composed of collagen type III, is the common way of visualizing myelofibrosis. HYA, like the collagens, is widely distributed in connective tissues. Little is known about the distribution of HYA in bone marrow.The aims of this thesis have been to determine how HYA is distributed in normal and malignant bone marrow, compared to reticulin staining, and to follow patients with chronic myeloproliferative diseases (CMPD) during two years treatment with anagrelide considering development of cellularity and fibrosis.In bone marrow biopsies from healthy volunteers, the controls, HYA was found in a pattern that was concordant with the reticulin staining.Comparing patients with different malignant diseases with and without bone marrow involvemen, HYA staining was found to be significantly stronger in both groups compared to the controls.The HYA scores were also significantly higher in the bone marrow of patients with de novo acute myeloid leukemia (AML), compared to the controls.There was a correlation between HYA and reticulin in the patients with de novo AML, and in the patients with different malignant diseases with and without bone marrow involvement as in the controls.Increase of HYA, reticulin and cellularity in the bone marrow of patients with CMPD after two years of treatment with anagrelide indicated progression of fibrosis. Anagrelide is a valuable drug for reduction of platelets but seems unable to stop progression of fibrosis and hypercellularity.HYA is an interesting molecule with properties not only contributing to the structure of extracellular matrix but also to cell signaling and behaviour, although the understanding of the detailed mechanisms is still incomplete.