Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis.
Though the diagnostic criteria of myeloid metaplasia with myelofibrosis (MMM) are now well established, the origin and pathophysiological mechanisms of this myeloproliferative disorder remain unclear. Concerning its pathophysiology, myeloproliferation and myelofibrosis are the intrinsic characteristics of the disease. Whereas the myeloproliferation was shown to result from a clonal amplification of primitive progenitor cells, fibroblast proliferation appeared to be polyclonal, thus suggesting that myelofibrosis was a reactive process. The myeloproliferation observed in MMM patients is characterized by an increased number of circulating CD34(+) hematopoietic progenitors. When cultured at high concentration without added exogenous growth factors, unpurified progenitors from MMM patients gave rise to spontaneous colonies of all myeloid lineages. Such an autonomous growth disappeared when purified CD34(+) progenitors were plated. These results suggested that growth factors are involved in the dysregulation of proliferation and/or differentiation of MMM hematopoietic progenitors. Cytokines such as PDGF, TGF-beta, and bFGF, produced mainly by megakaryocytes, have been proposed to be involved in the abnormal activation of fibroblasts, resulting in fibrosis. Recently the role of the fibrogenic cytokines, TGF-beta and bFGF, in the regulation of primitive hematopoiesis has been reported. The aim of this review is to address the question of the potential dual implication of TGF-beta and bFGF in the pathogenesis of both myelofibrosis and myeloproliferation in MMM patients.
Le Bousse-Kerdilès
M C
MC
INSERM U268, Hôpital Paul Brousse, 14, Avenue Paul-Vaillant Couturier, F-94800, Villejuif, France.
Martyré
M C
MC
D016207:Cytokines / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006801:Humans; D009196:Myeloproliferative Disorders / Q000209:etiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D055728:Primary Myelofibrosis / Q000150:complications* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2