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Altered oncoprotein expression and apoptosis in myelodysplastic syndrome
marrow cells
R Rajapaksa, N Ginzton, LS Rott and PL Greenberg
Department of Medicine, Stanford University Medical Center, CA, USA.
Ineffective hematopoiesis with associated cytopenias and potential
evolution to acute myeloid leukemia (AML) characterize patients with
myelodysplastic syndrome (MDS). We evaluated levels of apoptosis and of
apoptosis-related oncoproteins (c-Myc, which enhances, and Bcl-2, which
diminishes apoptosis) expressed within CD34+ and CD34- marrow cell
populations of MDS patients (n = 24) to determine their potential roles in
the abnormal hematopoiesis of this disorder. Marrow cells were
permeabilized and CD34+ and CD34- cells were separately analyzed by FACS to
detect: (1) a subdiploid (sub-G1) DNA population, and (2) expression of
Bcl-2 and c-Myc oncoproteins. Within the CD34+ subset, a significantly
increased percentage of cells demonstrated apoptotic/sub- G1 DNA content in
early (ie. refractory anemia) MDS patients compared with normal individuals
and AML patients (mean values: 9.1% > 2.1% > 1.2%). Correlated with
these findings, the ratio of expression of c-Myc to Bcl-2 oncoproteins
among CD34+ cells was significantly increased for MDS patients compared to
those from normal and AML individuals (mean values: 1.6 > 1.2 > 0.9).
Bcl-2 and c-Myc oncoprotein levels were maturation stage-dependent, with
high levels expressed within CD34+ marrow cells, decreasing markedly with
myeloid maturation. Treatment of seven MDS patients with the cytokines
granulocyte colony-stimulating factor plus erythropoietin was associated
with decreased levels of apoptosis within CD34+ marrow cells and may
contribute to the enhanced hematopoiesis in vivo that was shown. These
findings are consistent with the hypothesis that altered balance between
cell-death (eg, c-Myc) and cell-survival (eg, Bcl-2) programs were
associated with the increased degrees of apoptosis present in MDS
hematopoietic precursors and may contribute to the ineffective
hematopoiesis in this disorder, in contrast to decreased apoptosis and
enhanced leukemic cell survival in AML.
Volume 88,
Issue 11,
pp. 4275-4287,
12/01/1996
Copyright © 1996 by The American Society of Hematology
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