Naoyuki Anzai

Apoptosis in myelodysplasia: A paradox or paradigm

A growing body of evidence indicates that certain diseases are associated with increased apoptosis or inhibition of apoptosis. Among them, the myelodysplastic syndromes (MDS) are unique in that apoptosis is related, in apparently opposite directions, to the various facets of MDS. Ineffective hematopoiesis may be related to excessive intramedullary cell death via apoptosis and leukemic transformation conceivably results from escape from the apoptotic control. Future studies should be directed to define cellular susceptibility to and circumvention from apoptotic control mechanism(s).

Serial changes in endogenous erythropoietin levels in patients with myelodysplastic syndromes and aplastic anemia undergoing erythropoietin treatment

SummaryRecombinant human erythropoietin (rhEpo) was administered to 14 patients with myelodysplastic syndrome (MDS) and seven patients with aplastic anemia (AA). In 19 patients, doses of 6000 units were given intravenously three times a week (t.i.w.) with the dose being doubled up to 24000 units every 8 weeks until a response was obtained. RhEpo was given subcutaneously in two patients. Seven patients, four with MDS and three with AA, showed a significant response with an increase of hemoglobin concentration during therapy. The response occurred at doses of 12000 units in five and 24 000 units in two patients. Responding patients with both MDS and AA had a relatively low serum Epo (s-Epo) level prior to Epo therapy. MDS responders had either refractory anemia (RA) or RA with ring sideroblasts (RARS), while two of the Epo responders in AA had a severe form of the disease. However, since some of the Epo responders had a high initial s-Epo concentration, a high s-Epo level does not preclude the use of rhEpo. Serial determination of s-Epo levels showed a progressive decline in six of the seven responders even when they were on rhEpo therapy, while the s-Epo levels remained elevated or further increased with time in most nonresponders. RhEpo was well tolerated by all patients. The results suggest that rh-Epo is a safe and effective treatment for a certain proportion of patients with MDS and AA. Moreover, serial determination of s-Epo during therapy may be useful in monitoring and predicting the therapeutic effect of rhEpo.

Myelodysplastic syndrome (MDS)-associated inhibitory activity on haematopoietic progenitor cells : contribution of monocyte-derived lipid containing macrophages (MDLM)

We studied myelodysplastic syndrome‐associated inhibitory activity (MDS‐IA), which inhibited colony formation in vitro of normal granulocyte‐macrophage progenitors (CFU‐GM). When adherent marrow cells were incubated with fetal calf serum for 21–24 d. monocyte‐derived lipid containing huge macrophages (MDLM) developed. MDLM from MDS marrow (MDS‐MDLMs) and their conditioned medium (MDLM‐CM) consistently suppressed the growth of normal CFU‐GM colony formation. MDS‐IA was active on CFU‐GM during the S‐phase and relatively resistant to heating. Monoclonal antibody against H subunit (acidic) ferritin and polyclonal antibody against placental ferritin neutralized the inhibitory activity of MDS‐MDLMs. In addition, cell lysates of MDS‐MDLMs reacted to both monoclonal anti‐H subunit ferritin and polyclonal anti‐placental ferritin in Western blotting analysis, indicating that the inhibitory activity was predominantly acidic isoferritin.

Ca2+Mg2+-dependent endonuclease in marrow CD34 positive and erythroid cells in myelodysplasia

Endonucleases capable of producing internucleosomal DNA cleavage are one of the key enzymes in apoptosis. We examined endonuclease activities contained in nuclei of CD34+ and erythroid cells in the bone marrow (BM) from 12 patients with the myelodysplastic syndromes. The levels of Mg(2+)-dependent and acidic endonucleases showed little changes as compared with those from normal BM. By contrast, the level of Ca2+/Mg(2+)-dependent endonuclease was appreciably higher in MDS erythroid cells than normal counterparts, although the activity varied markedly in CD34+ and erythroid cells. Our results suggested that Ca2+/Mg(2+)-dependent endonuclease is related to ineffective erythropoiesis in MDS.