Expression and prognostic significance of Bcl‐2 family proteins in myelodysplastic syndromes

Abstract

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.

Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome

“…19 Similarly, Bcl2 expression was higher in AML cells arising in NHD13 mice ( Figure 3A). Therefore, the NHD13 mouse model of MDS parallels the temporal changes in BCL2-related proteins seen in human MDS.…”

Targeting NF-κB in hematologic malignancies

“…These technical aspects coupled to lower patient numbers may have accounted for the failure to detect a correlation between disease progression and NF-kB activation. [67][68][69] Indeed, the expression of proapoptotic proteins of the Bcl-2 family like Bak, Bad, and Bcl-X S has a favorable prognostic value in MDS, while the expression of antiapoptotic proteins like Bcl-2 and Bcl-X L is associated with unfavorable prognostic value, suggesting that apoptosis suppression could be implicated in the transformation of MDS to AML. 68 XIAP overexpression has also been implicated in apoptosis suppression and transformation of MDS to AML.…”

“…[67][68][69] Indeed, the expression of proapoptotic proteins of the Bcl-2 family like Bak, Bad, and Bcl-X S has a favorable prognostic value in MDS, while the expression of antiapoptotic proteins like Bcl-2 and Bcl-X L is associated with unfavorable prognostic value, suggesting that apoptosis suppression could be implicated in the transformation of MDS to AML. 68 XIAP overexpression has also been implicated in apoptosis suppression and transformation of MDS to AML. 69 A deregulation of FLIP and its splice variants in MDS bone marrow has also been shown recently.…”

Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

“…High Bcl-x L levels correlate with a poorer prognosis in patients with intermediate-grade lymphomas (Bairey et al, 1999), squamous cell carcinoma of the oropharyx (Aebersold et al, 2001), soft-tissue sarcomas (Kohler et al, 2002), and myelodysplastic syndrome (Boudard et al, 2002). Assays examining the ability of cells to regrow after drug treatment in vitro and in vivo have not only established the ability of Bcl-x L to enhance tumor cell repopulation after cytotoxic insults (Simonian et al, 1997;Liu et al, 1999), but also suggested that Bcl-x L is a more potent inducer of cell survival under these conditions (Simonian et al, 1997).…”