Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor

Abstract

Polycythemia vera (PV) is a clonal disease of the hematopoietic stem cell characterized by a hyperplasia of marrow erythropoiesis, granulocytopoiesis, and megakaryocytopoiesis. We previously reported that highly purified PV blood burst-forming units-erythroid (BFU-E) are hypersensitive to recombinant human interleukin-3 (rIL-3). Because these cells may be only a subset, and not representative of marrow progenitors, we have now studied partially purified marrow hematopoietic progenitor cells. Dose-response experiments with PV marrow BFU-E showed a 38-fold increase in sensitivity to rIL-3 and a 4.3-fold increase in sensitivity to recombinant human erythropoietin (rEpo) compared with normal marrow BFU-E. In addition, PV marrow colony- forming units-granulocyte-macrophage (CFU-GM) and CFU-megakaryocyte (CFU-MK) also showed a marked hypersensitivity to rIL-3 and to human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Dose-response curves with rGM-CSF and blood BFU-E showed a 48-fold increase in sensitivity. No effect of rIL-4, rIL-6, human recombinant granulocyte-CSF (rG-CSF), or macrophage-CSF (rM-CSF) was evident, nor was there any effect of PV cell-conditioned medium on normal BFU-E, when compared with normal cell-conditioned medium. Autoradiography with 125I-rEpo showed an increase in Epo receptors after maturation of PV BFU-E to CFU-E similar to that shown with normal BFU-E, but no increase of specific binding of 125I-rIL-3 by PV CD34+ cells was seen compared with normal CD34+ cells. These studies show that PV marrow hematopoietic progenitor cells are hypersensitive to rIL-3 and rGM-CSF, similar to PV blood BFU-E. While the mechanism does not appear to be due to enhanced binding of rIL-3, the hypersensitivity of PV progenitor cells to IL-3 and GM-CSF may be a key factor in the pathogenesis of PV.

The predictive value of clonogenic stem cell assays for the diagnosis of polycythaemia vera

“…This phenomenon is explained by the increased sensitivity of the pathological progenitor cells to EPO (Casadevall et al, 1982;Weinberg et al, 1989). The same phenomenon was also observed after addition of a cytokine cocktail, confirming the hypersensitivity of the affected progenitor cell to other cytokines including interleukin (IL) 1, IL-3, stem cell factor, insulin-like growth factor-1 and granulocyte-macrophage colony-stimulating factor (Dai et al, 1991(Dai et al, , 1992Correa et al, 1994;Dai et al, 1994).…”

Hypersensitivity of megakaryocyte progenitors to thrombopoietin in essential thrombocythemia

“…In myeloproliferative disorders, it has been suggested that hematopoietic progenitor cells are hypersensitive to certain cytokines: erythroid progenitors to erythropoietin and interleukin-3(IL-3) in polycythemia vera [4,5]; myeloid and megakaryocyte progenitors to IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in polycythemia vera [6]; myeloid progenitors to GM-CSF in juvenile chronic myeloid leukemia [7]. In ET, Kobayashi et al previously reported megakaryocyte progenitors are hypersensitive to IL-3 [8].…”

Towards a molecular understanding of polycythemia rubra vera

“…Several investigators have shown that, apart from erythropoietin and IGF-1, PV cells are hypersensitive to hematopoietic growth factors including interleukin-3, granulocyte/monocyte colony stimulating factor (GM-CSF), stem cell factor (SCF) and thrombopoietin [54±57]. Dai et al have shown that erythroid colony forming cells from PV bone marrow are up to 100-fold more sensitive to interleukin-3 than normal cells in serum-containing medium [54,55]. Likewise, in the same system, PV BFU-E are 48 times more sensitive to GM-CSF than their normal counterparts [55].…”