The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis

Abstract

Acute myelofibrosis is often associated with acute megakaryoblastic leukemia (AMKBL). Although the exact mechanism for the progression of myelofibrosis in AMKBL is unclear, certain humoral factors from megakaryoblastic cells, the precursors of platelets, may be involved in the enhancement of collagen synthesis by bone marrow fibroblasts. The present study, therefore, is an investigation of the possible pathogenic role of transforming growth factor-beta (TGF-beta), known to be a very potent collagen-stimulating factor found in platelets in the myelofibrosis of AMKBL. The results obtained were as follows: (1) Conditioned media from peripheral megakaryoblasts taken from an AMKBL patient and from established megakaryoblast cell lines (MEG-01) had much greater stimulatory effects on collagen synthesis in bone marrow fibroblasts than conditioned media from other leukemic cell types. (2) Based on an assessment of soft agar colony formation, there was greater TGF-beta activity in media that had been conditioned from megakaryoblasts than in media from other leukemic cell types. (3) When compared with other leukemic-cell types, megakaryoblasts showed substantially greater expression of TGF-beta mRNA that was hybridized at 2.5 kb with a TGF-beta cDNA probe, and TGF-beta polypeptides were detected at 13 Kd with anti-TGF-beta antibodies. (4) The addition of the anti-TGF-beta antibody inhibited the stimulatory effects of the megakaryoblast conditioned medium on collagen synthesis in bone marrow fibroblasts. These results clearly suggest that megakaryoblasts produce and secrete an active form of TGF-beta and stimulate collagen synthesis in bone marrow fibroblasts in a paracrine manner.

Reduced responsiveness of bone marrow megakaryocyte progenitors to platelet‐derived transforming growth factor β1, produced in normal amount, in patients with essential thrombocythaemia

“…b). It has been previously demonstrated that the production of platelet-derived growth factor and of TGF-pl is increased in patients affected by myelofibrosis with myeloid metaplasia (Martyre et al, 1991) and in patients with acute megakaryoblastic leukaemia (Terui et al, 1990). Interestingly.…”

Myeloperoxidase‐positive acute megakaryoblastic leukemia in a dog

“…32,33 One cause may be increased concentrations of transforming growth factor-beta, a potent promoter of collagen synthesis by bone marrow fibroblasts, which is stored in platelet a granules. 33,34 In canine cases of acute megakaryoblastic leukemia, marrow fibrosis due to accumulation of reticulin or collagen is a variable finding. 10,19 In the present case, no evidence of bone marrow fibrosis was found, although the 2 first failed attempts to obtain a bone marrow aspirate could suggest its presence.…”

The production of tissue inhibitors of metalloproteinases (TIMPs) in megakaryopoiesis: possible role of platelet‐ and megakaryocyte‐derived TIMPs in bone marrow fibrosis

“…Their findings also suggested that PDGF released from the platelets of some patients with myeloproliferative disorders inappropriately stimulated fibroblasts to divide and secrete collagen. Kimura et al (1988) reported that the growth and stromal protein synthesis of fibroblasts, which cause marrow fibrosis, were stimulated by TGF-b, PDGF and EGF, and Terui et al (1990) observed the production of TGF-b in patients with acute megakaryoblastic leukaemia.…”