The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) on megakaryopoiesis in normal subjects and patients with myelodysplasia and acute myeloid leukaemia

Abstract

The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) on megakaryopoiesis in normal subjects and patients with myelodysplasia and acute myeloid leukaemia Summary. Mpl ligand is a recently cloned haemopoietic growth factor that stimulates megakaryopoiesis in vitro and in vivo. We describe the in vitro effect of a truncated form of Mpl ligand, recombinant human megakaryocyte growth and development factor (rHuMGDF), on megakaryopoiesis in bone marrow from normal subjects and patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). We used both semi-solid and suspension culture techniques to assess the effect of pegylated (PEG) rHuMGDF on megakaryocyte colony growth (CFU-Mk) and on the production of CD61 þ cells in 7 d suspension cultures. PEG rHuMGDF increased CFU-Mk growth and CD61 þ cell production in a dose-dependent fashion in all normal marrows tested. Normal CFU-Mk growth was increased threefold with the addition of 10 ng/ml PEG rHuMGDF to cultures and CD61 þ cells were increased 8-10-fold by the

Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death

“…In many MDS cases, megakaryocyte progenitor growth was unresponsive to recombinant TPO. 22,24 This defective response is probably due to deregulated TPOreceptor-mediated signaling pathways, 25 as a lack of serum TPO, 26 a decreased expression of c-mpl (TPO-receptor) 22 or mutations in c-mpl 25 have been excluded.…”

Treatment of Myelodysplastic Syndrome with Thrombomimetic Drugs

“…With the lesson learned from EPO, it has been thus considered that stimulating progenitor proliferation and maturation with thrombopoietic growth factors could at least partially overcome these two defects typical of MDS as indicated by in vitro observations (22)(23).…”

On Raising the “Dust of Blood”: From Unrevealing Thrombopoiesis to Treatment of Thrombocytopenias With Thrombomimetic Drugs

“…8 This immune reaction provoked severe thrombocytopenia 8 and stopped further therapeutic applications of these two agents, notwithstanding their obvious activity both in healthy volunteers and in patients with thrombocytopenia secondary to chemotherapy, 9,10 as well as immune thrombocytopenic purpura (ITP) 11 and myelodysplastic syndromes (MDS). 12 The quest for active and non-immunogenic thrombomimetic agents led to the development of the secondgeneration TPO mimetics, deprived of sequence homology to endogenous TPO: TPO nonpeptide mimetics (eltrombopag, NIP-004, and AKR-501), TPO peptide mimetics (AMG 531 and Fab59), and TPO agonist antibodies. 7,13 Two of these agents, eltrombopag and romiplostim, achieved health authority approval for several indications.…”