TY - JOUR
T1 - Expression of apoptosis proteins in chronic myelogenous leukemia associations and significance
AU - Ravandi, Farhad
AU - Kantarjian, Hagop M.
AU - Talpaz, Moshe
AU - O'Brien, Susan
AU - Faderl, Stefan
AU - Giles, Francis J.
AU - Thomas, Debbie
AU - Cortes, Jorge
AU - Andreeff, Michael
AU - Estrov, Zeev
AU - Rios, Mary Beth
AU - Albitar, Maher
PY - 2001/6/1
Y1 - 2001/6/1
N2 - BACKGROUND. The mechanisms favoring the growth advantage of Philadelphia chromosome positive cells over normal cells in chronic myelogenous leukemia (CML) are not fully elucidated but could be due partly to altered apoptosis and longer survival of CML clones. Also, little is known about the biologic characteristics of disease progression in CML. Bcl-2 expression has been demonstrated to exert an antiapoptotic effect resulting in increased cell survival. Other proteins such as Bax and Bad are proapoptotic proteins. Fas, a cell surface protein, can be triggered by an appropriate death-promoting ligand (FasL) to activate downstream caspases pivotal in initiation of programmed cell death. Although the mechanisms underlying cellular proliferative and apoptotic pathways are complex, with involvement of multiple interlocking proteins, the relative expression of pro- and anti-apoptotic proteins may have an influence on disease progression. This study aimed to determine whether the changes in the cellular expression of Bcl-2, Bax, and Fas correlate with caspase-3 activity and disease progression in CML, or with response to interferon (IFN)-α therapy and prognosis in early chronic phase CML. METHODS. Bcl-2, Bax, and Fas expression were measured on whole cell lysates from bone marrow mononuclear cell fractions by Western blot analysis and quantitative radioimmunoassay. Caspase-3 activity was determined using the DEVD system. Specimens from 203 patients with CML were examined. These included 130 patients in early chronic phase disease (ECP; diagnosis to therapy, ≤12 months), 33 patients in late chronic phase (diagnosis to therapy, > 12 months), 27 patients in accelerated phase, and 13 patients in blastic phase. Correlations between apoptosis proteins and CML phases, risk groups in ECP, and response to IFN-α therapy and survival in ECP were investigated by standard statistical methods, and positive findings were assessed by multivariate analysis. RESULTS. Levels of Bcl-2, Fas, Bax, and caspase-3 activity did not correlate with disease progression. Among patients in ECP, higher Fas levels correlated with poorer risk groups (P = 0.05) and higher caspase-3 activity correlated with better risk groups (P = 0.048). With IFN-α therapy, major cytogenetic responses were noted in 30% of patients with high Fas and 53% with low Fas (P = 0.016) and failure to achieve a complete hematologic response (CHR) in 25% versus 2% (P = 0.0001). Survival was shorter with high Fas levels (5-year rates, 71% vs. 52%; P = 0.002), and the independent poor prognostic significance of high Fas levels was confirmed by multivariate analysis (P = 0.014). Response to IFN-α therapy and survival were not significantly different by different levels of Bcl-2, Bax, or caspase-3 activity. CONCLUSIONS. High Fas levels were associated with intrinsically worse disease at diagnosis, whereas high caspase-3 activity was associated with good risk disease. In ECP CML, high Fas levels were associated with significantly worse response to IFN-α therapy and with significantly worse survival. The influence of these cellular proteins and caspase-3 activity on apoptosis in CML is complex and merits further investigation
AB - BACKGROUND. The mechanisms favoring the growth advantage of Philadelphia chromosome positive cells over normal cells in chronic myelogenous leukemia (CML) are not fully elucidated but could be due partly to altered apoptosis and longer survival of CML clones. Also, little is known about the biologic characteristics of disease progression in CML. Bcl-2 expression has been demonstrated to exert an antiapoptotic effect resulting in increased cell survival. Other proteins such as Bax and Bad are proapoptotic proteins. Fas, a cell surface protein, can be triggered by an appropriate death-promoting ligand (FasL) to activate downstream caspases pivotal in initiation of programmed cell death. Although the mechanisms underlying cellular proliferative and apoptotic pathways are complex, with involvement of multiple interlocking proteins, the relative expression of pro- and anti-apoptotic proteins may have an influence on disease progression. This study aimed to determine whether the changes in the cellular expression of Bcl-2, Bax, and Fas correlate with caspase-3 activity and disease progression in CML, or with response to interferon (IFN)-α therapy and prognosis in early chronic phase CML. METHODS. Bcl-2, Bax, and Fas expression were measured on whole cell lysates from bone marrow mononuclear cell fractions by Western blot analysis and quantitative radioimmunoassay. Caspase-3 activity was determined using the DEVD system. Specimens from 203 patients with CML were examined. These included 130 patients in early chronic phase disease (ECP; diagnosis to therapy, ≤12 months), 33 patients in late chronic phase (diagnosis to therapy, > 12 months), 27 patients in accelerated phase, and 13 patients in blastic phase. Correlations between apoptosis proteins and CML phases, risk groups in ECP, and response to IFN-α therapy and survival in ECP were investigated by standard statistical methods, and positive findings were assessed by multivariate analysis. RESULTS. Levels of Bcl-2, Fas, Bax, and caspase-3 activity did not correlate with disease progression. Among patients in ECP, higher Fas levels correlated with poorer risk groups (P = 0.05) and higher caspase-3 activity correlated with better risk groups (P = 0.048). With IFN-α therapy, major cytogenetic responses were noted in 30% of patients with high Fas and 53% with low Fas (P = 0.016) and failure to achieve a complete hematologic response (CHR) in 25% versus 2% (P = 0.0001). Survival was shorter with high Fas levels (5-year rates, 71% vs. 52%; P = 0.002), and the independent poor prognostic significance of high Fas levels was confirmed by multivariate analysis (P = 0.014). Response to IFN-α therapy and survival were not significantly different by different levels of Bcl-2, Bax, or caspase-3 activity. CONCLUSIONS. High Fas levels were associated with intrinsically worse disease at diagnosis, whereas high caspase-3 activity was associated with good risk disease. In ECP CML, high Fas levels were associated with significantly worse response to IFN-α therapy and with significantly worse survival. The influence of these cellular proteins and caspase-3 activity on apoptosis in CML is complex and merits further investigation
KW - Apoptosis
KW - Bax
KW - Bcl-2
KW - Caspase-3
KW - Chronic myelogenous leukemia
KW - Fas
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U2 - 10.1002/1097-0142(20010601)91:11<1964::AID-CNCR1221>3.0.CO;2-B
DO - 10.1002/1097-0142(20010601)91:11<1964::AID-CNCR1221>3.0.CO;2-B
M3 - Article
C2 - 11391574
AN - SCOPUS:0035371214
SN - 0008-543X
VL - 91
SP - 1964
EP - 1972
JO - Cancer
JF - Cancer
IS - 11
ER -