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A severe and consistent deficit in marrow and circulating primitive
hematopoietic cells (long-term culture-initiating cells) in acquired
aplastic anemia
JP Maciejewski, C Selleri, T Sato, S Anderson and NS Young
Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD
20892-1652, USA.
We examined the stem cell compartment of patients with acquired aplastic
anemia (AA) using the long-term culture-initiating cell assay (LTC-IC), in
parallel with measurements of CD34+ cells and mature hematopoietic
progenitors. Secondary colonies from cells surviving 5 weeks of long-term
bone marrow culture (LTBMC) were determined for the peripheral blood (PB)
of 68 AA patients and 13 normal controls and for BM of 49 AA patients and
14 controls; because of low cell numbers, formal limiting dilution analysis
could only be performed in 10 patients. The relationship of cell input in
LTBMC and the output of secondary colonies was linear, allowing
quantification of LTC-IC number from bulk cultures. Secondary colony
formation was markedly abnormal in severe AA. In contrast to 7.8
colony-forming cells (CFC)/10(5) mononuclear cells in normal BM and 0.14
CFC/10(5) normal PB mononuclear cells, patients with severe disease showed
0.024 CFC/10(5) in BM and 0.0068 CFC/10(5) in PB. Under limiting dilution
conditions, patients' cells also showed markedly lower colony-forming
ability. In contrast to 4.3 +/- 1 colonies/normal LTC-IC, we obtained only
1.27 +/- 0.09 and 2.0 +/- 0.35 colonies from BM of acute and recovered
cases, respectively. These values were used to extrapolate LTC-IC numbers
from secondary colony formation in suspension cultures. In PB, calculated
LTC-IC were decreased 7.4-fold in new and relapsed severe AA and 2.8- fold
in recovered AA. In BM, LTC-IC were decreased 10-fold in new and relapsed
AA and sixfold in recovered cases. Compared with measurements obtained on
presentation, LTC-IC were lower in post-treatment samples from patients who
had failed to recover after intensive immunosuppression and relatively
higher in cases at relapse. In recovered patients, LTC-IC number increased
but remained below the normal range in 20 of 25. In patients studied
serially for 3 to 12 months after treatment, LTC-IC numbers remained stable
but low. LTC-IC number correlated with concurrently determined CD34+ cell
number and primary hematopoietic colony formation. These results indicate
that stem cell numbers, as quantitated by the LTC-IC assay, are markedly
diminished in number in all severe AA. Additionally, the function of the
stem cell or the stem cell compartment in AA is also abnormal, as inferred
from the low clonogenic potential in secondary colony assays. Early
hematologic improvement in some patients occurs without increasing numbers
of LTC-IC, and a minority of recovered cases show apparent repopulation of
the LTC-IC compartment years after treatment.
Volume 88,
Issue 6,
pp. 1983-1991,
09/15/1996
Copyright © 1996 by The American Society of Hematology
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