The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia

Abstract

The Wilms tumor gene wt1 and the protooncogene bcl-2 are upregulated in acute myeloid leukemia (AML) and are known to regulate or to inhibit the onset of apoptosis. Since wt1 has been shown to regulate the expression of bcl-2, we investigated the association of the expression of these genes and their prognostic relevance in AML. Leukemic blasts from the bone marrow of 152 patients with newly diagnosed AML were analyzed for bcl-2 and wt1 mRNA expression using RT-PCR and quantitative PCR. Therapy outcome was correlated with the level of bcl-2 and wt1 transcripts. Bcl-2-specific mRNA was detectable in 127/152 (84%) patients and wt1 mRNA in 113/152 (74%) patients with AML. In monocytic subtypes the frequency of bcl-2 and wt1 transcripts was significantly lower. The expression of bcl-2 mRNA was correlated significantly with that of wt1 mRNA (P Ͻ 0.0001). In AML patients Ͻ60 years, high expression of bcl-2 and wt1 was associated with a reduced rate of continuing complete remission (CCR, P = 0.002 and P = 0.005, respectively) and increased death rate (P = 0.0002 and P = 0.04, respectively) in contrast to patients Ͼ60 years, where the expression of bcl-2 or wt1 had no prognostic impact. Based on the coexpression of bcl-2 and wt1, we established a prognostic model defining three risk groups with significant differences in CCR rate (P = 0.01), overall survival (P Ͻ 0.04) and disease-free survival (P Ͻ 0.03). Thus, bcl-2 and wt1 mRNA expression are associated with response and long-term outcome in AMLs. The coexpression of these genes allows determination of prognostic groups with high predictive value for overall and disease-free survival. Leukemia (2002) 16, 846-854.

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…In this regard, the WT1 gene has been shown to repress the expression of the pro-apoptotic gene Bak 40 and to upregulate the antiapoptotic genes Bcl-2 (ref. 41) and A1/BFL1 (ref. 42) in myeloid lineage cells.…”

“…These studies, including WT1 peptide and WT1-targeted dendritic cell vaccine trials, have unequivocally established that CD8 þ T-cell immune responses specific to WT1 can be induced by active immunization in a substantial number of AML patients. 14 In those patients, multiple WT1 CTL epitopes have been recognized as immunogenic (including WT1 [37][38][39][40][41][42][43][44][45] , WT1 [126][127][128][129][130][131][132][133][134] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ), demonstrating the excellent in vivo immunostimulatory potential of WT1 (Table 1). 14,72 This is further supported by the capacity to induce WT1-specific CD4 þ helper T-cell immunity in patients with AML through active immunization.…”

“…87 These findings were corroborated by the later work of Rezvani et al, 73 who observed spontaneous T-cell responses to PR1 and WT1 [126][127][128][129][130][131][132][133][134] in two out of eight patients before immunization with a combined PR1/WT1 peptide vaccine. 73 In a separate study, the same group found that such CTL responses were not limited to the immunodominant WT1 [126][127][128][129][130][131][132][133][134] epitope, but could also be directed against other HLA-A*0201-restricted WT1-derived epitopes (WT1 [37][38][39][40][41][42][43][44][45] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ). 88 A similar observation was made regarding PRAME, which is known to contain at least four different HLA-A*0201-restricted epitopes that can be naturally recognized (PRA …”

Wilms' Tumor 1 Suppressor Gene Mediates Antiestrogen Resistance via Down-Regulation of Estrogen Receptor-α Expression in Breast Cancer Cells

“…The expression of WT1 in breast cancer has both prognostic and biological effects. Several groups have found that high levels of WT1 expression in breast cancer are associated with a worse prognosis (7)(8)(9). This is possibly due to a proliferation and survival effect provided by WT1 because down-regulation of WT1 inhibits breast cancer growth (10).…”

Functional Role of WT1 in Prostate Cancer

“…Many studies have shown elevated WT1 expression in diverse cancer types, including leukemia (34-37), breast (38)(39)(40), Ewing sarcoma (41), ovarian (42), mesothelioma, and pulmonary adenocarcinomas (43). Additionally, WT1 is being investigated as a potential prognostic marker for both leukemia and breast cancer (39,44).…”