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Prolonged survival of B-lineage acute lymphoblastic leukemia cells is
accompanied by overexpression of bcl-2 protein
D Campana, E Coustan-Smith, A Manabe, M Buschle, SC Raimondi, FG Behm, R Ashmun, M Arico, A Biondi and CH Pui
Department of Hematology-Oncology, St Jude Children's Research Hospital,
Memphis, TN 38101.
Overexpression of bcl-2 delays the onset of apoptosis in
lymphohematopoietic cells. We measured levels of bcl-2 protein in normal
and leukemic human B-cell progenitors with a specific monoclonal antibody
and flow cytometry. Normal immature B cells had low levels of bcl-2
protein; the intensity of fluorescence, expressed as molecules of soluble
fluorochrome per cell, within CD10+ cells was 3,460 +/- 1,050 (mean +/- SD;
5 samples). In 16 cases of B-lineage acute lymphoblastic leukemia (ALL),
cells had levels of bcl-2 that were strikingly higher than those of their
normal counterparts (33,560 +/- 14,570; P < .001 by t-test analysis). We
next investigated whether the intensity of bcl-2 expression correlated with
the resistance of immature B cells to in vitro culture. In 12 cases of
B-lineage ALL, the cells recovered after 7 days of culture on allogeneic
bone marrow stromal layers were 69% to 178% (median, 95.5%) of those
originally seeded. Prolonged survival of leukemic cells in vitro was
observed even in the absence of stromal layers in 6 of these 12 cases; the
intensity of bcl-2 protein expression in these cases was 45,000 +/- 13,270,
compared with 21,500 +/- 7,260 in the 6 cases in which greater than 99.5%
of cells rapidly died by apoptosis under the same culture conditions (P =
.003). Five immature B-cell lines, continuously growing in the absence of
stroma, had the highest bcl-2 expression (79,400 +/- 20,330). By contrast,
most normal CD19+, sIg-immature B cells died despite the presence of bone
marrow stromal layers; 9.7% to 28.2% were recovered after 7 days of culture
in three experiments. We conclude that abnormal bcl-2 gene expression
influences the survival ability of B-cell progenitors. This may contribute
to leukemogenesis and explain the aptitude of leukemic lymphoblasts to
expand outside the bone marrow microenvironment.
Volume 81,
Issue 4,
pp. 1025-1031,
02/15/1993
Copyright © 1993 by The American Society of Hematology
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