Expression and prognostic significance of Bcl-2 family proteins in myelodysplastic syndromes.
Excessive apoptosis is implicated in the pathogenesis of myelodysplastic syndromes (MDS). We assessed by flow cytometry the expression of several members of the Bcl-2 family in bone marrow mononuclear cells (BMMNC) of 168 MDS samples at diagnosis. The proteins studied were Bcl-2, Bcl-xL (anti-apoptotic), Bax, Bad, Bak, and Bcl-xS (pro-apoptotic). The percentage of BMMNC expressing Bcl-2 and Bcl-xL was higher in refractory anemia with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML) than in refractory anemia (RA) and RA with ringed sideroblasts (RAS). Conversely pro-apoptotic proteins Bad, Bak, and Bcl-xS were detected in a higher percentage of cells in RA and RAS. RA and RAS were associated with an increased Bcl-xS/Bcl-xL ratio. The expression of anti-apoptotic proteins was also correlated with that of CD34 and P170 and with the percentage of blast cells. Two-color analyses demonstrated that CD34 and Bcl-2 were usually expressed in the same cells. No significant correlation was found with cytogenetic abnormalities. Higher expression of pro-apoptotic Bcl-2-family proteins (Bak, Bad, Bcl-xS) and higher Bcl-xS/Bcl-xL ratio were associated with longer survival and decreased risk of leukemic transformation in univariate analysis, whereas expression of anti-apoptotic proteins was associated with decreased survival. Consequently Bcl-2 proteins expression was well correlated with the International Prognostic Scoring System (IPSS). Our data confirm that the control of apoptosis is deregulated in MDS cells. Moreover, the study of markers such as CD34 (or Bcl-2), Bcl-xL, and Bcl-xS provides additional prognostic information.
Faculté de Médecine J. Lisfranc, Laboratoire Mort Cellulaire et Néoplasies, 15 rue Ambroise Paré, 42023 Saint-Etienne Cedex 02, France. delphine.boudard@univ-st-etienne.fr
Delphine
D
Boudard
Christian
C
Vasselon
Marie-Françoise
MF
Berthéas
Jérôme
J
Jaubert
Christiane
C
Mounier
Jacqueline
J
Reynaud
Annie
A
Viallet
Sylviane
S
Chautard
Denis
D
Guyotat
Lydia
L
Campos
D000328:Adult; D000753:Anemia, Refractory / Q000503:physiopathology; D018952:Antigens, CD34 / Q000032:analysis; D002352:Carrier Proteins / Q000032:analysis; D005434:Flow Cytometry; D006801:Humans; D007951:Leukemia, Myeloid / Q000503:physiopathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000503:physiopathology; D008565:Membrane Proteins / Q000032:analysis; D015999:Multivariate Analysis; D009190:Myelodysplastic Syndromes / Q000503:physiopathology*; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D018952:Antigens, CD34; C494819:BAD protein, human; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein