Bcl-2 expression by myeloid precursors in myelodysplastic syndromes: relation to disease progression.
METHODS
the bcl-2 oncogene blocks apoptosis in various cell types and is expressed by normal myeloid precursors, declining with maturation. To investigate whether bcl-2 plays a role in the increase of myeloblasts in myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML), we studied bcl-2 expression in initial (pre-therapy) bone marrow biopsies from MDS at early (refractory anemia, RA, with or without ring sideroblasts) and advanced stages (RA with excess blasts, and in transformation). Sequential biopsies were also studied to evaluate the effect of time or disease progression, including evolution to AML, or therapy with granulocyte colony stimulating factor (G-CSF). Early myeloid precursors (EMPs), predominantly myeloblasts, were identified in paraffin sections after immunostaining; bcl-2-positive EMPs were enumerated as a percentage of all EMPs (Bcl-2%), and by their absolute frequency per x 900 microscopic field (Bcl-2 index).


RESULTS
in initial biopsies, the Bcl-2% and Bcl-2 index in early MDS (9.9+/-2.6 and 1.4+/-0.6, respectively; mean+/-S.E.) were significantly lower than in advanced MDS (26.4+/-3.6, 4.6+/-1.4), but similar to controls (8.1+/-0.3 and 0.8+/-0.1). The Bcl-2% and Bcl-2 index in three patients with AML evolved from MDS (57.4+/-17.9 and 85.1+/-62.4) were similar to values for seven patients with de novo AML (63.0+/-10.0, 98.4+/-29.8) and significantly higher than values for other groups. Bcl-2% showed relative increments with time or disease progression (range, 21-273%; 11 of 18 sequential biopsies from six of ten MDS patients), which was not clearly altered by G-CSF therapy (four of six patients with, two of four patients without treatment).


CONCLUSIONS
bcl-2 expression by EMPs (in both proportion and absolute number) correlated with initial MDS stage, progressed over time independent of G-CSF therapy, and was associated with evolution to AML. These data provide support for the hypothesis that MDS progression is related to accumulation of immature myeloid cells with increased bcl-2 expression and decreased apoptosis.
Department of Pathology, Stanford University Medical Center and VA Palo Alto Health Care System, CA 94304, USA.
R E
RE
Davis
P L
PL
Greenberg
D000208:Acute Disease; D001706:Biopsy; D018450:Disease Progression; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013997:Time Factors
D019253:Proto-Oncogene Proteins c-bcl-2; D016179:Granulocyte Colony-Stimulating Factor