Fibroblast dynamics as an in vitro screening platform for anti‐fibrotic drugs in primary myelofibrosis

Abstract

Although the cause for bone marrow fibrosis in patients with myelofibrosis remains controversial, it has been hypothesized that it is caused by extensive fibroblast proliferation under the influence of cytokines generated by the malignant megakaryocytes. Moreover, there is no known drug therapy which could reverse the process. We studied the fibroblasts in a novel system using the hanging drop method, evaluated whether the fibroblasts obtain from patients are part of the malignant clone of not and, using this system, we screen a large library of FDA‐approved drugs to identify potential drugs candidates that might be useful in the treatment of this disease, specifically which would inhibit fibroblast proliferation and the development of bone marrow fibrosis. We have found that the BM fibroblasts are not part of the malignant clone, as previously suspected and two immunosuppressive medications—cyclosporine and mycophenolate mophetil, as most potent suppressors of the fibroblast collagen production thus potentially inhibitors of bone marrow fibrosis production in myelofibrosis.

Castleman’s disease in the HIV-endemic setting

“…The chi-squared test was used to compare categorical variables between the groups while independent t -test used for normally distributed continuous variable and Mann–Whitney test for continuous variables with skewed distribution, as previously described. 9 – 12 …”

Transforming growth factor β‐mediated micromechanics modulates disease progression in primary myelofibrosis

“…[12,14,15] In support of these data, we have recently shown that the fibroblasts involved in this process do not derive from the malignant clone but seem to represent over-stimulated normal cells. [16] The main cytokine believed to be involved in generation of PMFassociated fibrosis is TGF β. [17] TGF-β acts on fibroblast physiology by increasing synthesis of collagen, type I, III, IV and V, as well as production of fibronectin, proteoglycans and tenascin.…”

Overview of the Side-Effects of FDA- and/or EMA-Approved Targeted Therapies for the Treatment of Hematological Malignancies

“…Nonetheless, these drugs have been shown to be very active in lymphoid diseases, thus having potential clinical use if the side-effect profile can be better managed [ 29 ]. An important drug that revolutionized symptom management in primary myelofibrosis is ruxolitinib [ 30 , 31 , 32 ]. This drug inhibits both JAK1 and JAK2, thus reducing proinflammatory cytokine levels and, because of this, the size of the spleen and severity constitutional symptoms.…”