The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS

Bone marrow CD34(+) cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 pat ients with myelodysplastic syndrome (MDS) and acute myeloid leukemia second ary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significa ntly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51. 2% [25.2%-76.6%]) compared with NBM (16.7% [3.4%-35.3%], P < .0001). In RA/ RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5 %-47.8%]; apoptosis: proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB , this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (4 0.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML w as associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%] ; P < .0001) and proliferation (16.8% [1.9%-75.8%] P = .04; ratio 1.69 [0.1 6-12.21]), Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl- 2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P = .06), whereas disease progression w as associated with significantly reduced ratios (1.16 [0.06-3.32]; P < .000 1) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2 /Bcl-X ratio were inversely correlated with both International Prognostic S coring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend to ward an association between Bcl-2-related protein expression and apoptosis (P = .07). This study indicates that MDS progression arises through multipl e hits that alter levels of CD34(+) cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apopt osis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rath er than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2-related protein rati os, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS. (C) 2000 by The American Society of Hematology.