Inhibition of Bone Marrow Stem Cell Growth In Vitro by Methylmalonic Acid: a Mechanism for Pancytopenia in a Patient with Methylmalonic Acidemia

摘要

Summary: A 7-week-old infant with methylmalonic acidemia had pancytopenia and hypoplastic bone marrow. The patient responded to large doses of vitamin B12 treatment, and within 3 wk, the blood counts and bone marrow cellularity returned to normal. To understand the mechanism of marrow depression in this infant, we examined the effect of the patient's plasma and methylmalonic acid itself on the in vitro growth of bone marrow-committed stem cells. The patient's plasma obtained before B12 treatment completely inhibited the marrow cell growth, whereas the posttreatment plasma showed no inhibition. Methylmalonic acid when added to the culture dishes in concentrations comparable to those reported in plasma of methylmalonic acidemia patients, inhibited growth of marrow stem cells in a concentration-dependent fashion. On the other hand, 16 to 18 hr incubation of cells in the same concentration of methylmalonic acid did not affect the recovery or viability of the cells. The observations suggest that methylmalonic acid is inhibitory to the proliferation of marrow stem cells. The mechanism of inhibition is yet to be elucidated.Speculation: MMA at a concentration comparable to that reported in patients with methylmalonic acidemia inhibited in vitro growth of marrow hemopoietic cells, but overnight incubation of the cells in MMA at the same concentration did not reduce the number of viable cells determined by the trypan blue dye exclusion test. It appears, therefore, that MMA within the range of concentration tested is not immediately cytotoxic. Its inhibitory action thus seems to require longer cell contact hours than the 16 to 18 hr we used, and it may be directed against rapidly proliferating cell population. The potential mechanisms of inhibition are unknown and more work is needed to understand the interaction of MMA with hemopoietic cells.