TY - JOUR
T1 - BAX and PKCα modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia
AU - Kornblau, Steven M.
AU - Vu, Ha T.
AU - Ruvolo, Peter
AU - Estrov, Zeev
AU - O'Brien, Susan
AU - Cortes, Jorge
AU - Kantarjian, Hagop
AU - Andreeff, Michael
AU - May, W. Stratford
N1 - Copyright:
Copyright 2004 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 2000/4
Y1 - 2000/4
N2 - Previously, we demonstrated that the level of BCL2 expression is prognostic in acute myelogenous leukemia (AML). High levels of BCL2 correlate with an adverse outcome when associated with favorable and intermediate prognosis cytogenetics (FIPC), whereas low levels portend an adverse outcome when associated with unfavorable cytogenetics (UC). Because BCL2 function can be modulated by dimerization with family members, like BAX, or by phosphorylation by protein kinase C α (PKCα), we hypothesize that the relative expression of these proteins in primary leukemic cells might alter the prognostic impact of BCL2 expression. We therefore measured BAX and PKCα protein levels in peripheral blood mononuclear cell lysates from 165 newly diagnosed AML patients and correlated the expression of these proteins with BCL2 expression, patient survival, and remission induction success. Expression levels of BAX and PKCα were normalized against a control cell line, K562. BAX and PKCα expression levels were heterogeneous and did not correlate with the percentage of blasts in the sample (R2 = 0.01 and <0.01). The median expression of both was similar across FAB groups but the range was greater for M4. A similar distribution of expression was observed in all cytogenetic groups, except that patients with inversion 16 demonstrated lower levels of BAX. Individually, neither PKCα nor BAX expression was prognostic of response to induction therapy or survival. A similar outcome was obtained when patients were stratified by cytogenetics into FIPC and UC groups. However, the ratio of either BCL2:BAX (B2:BX) or PKCα*B2:BX (PK*B2:BX) was highly prognostic. Patients with FIPC and a lower ratio (less than median) of either B2:BX or PK*B2:BX had a significantly higher remission induction rate (88 versus 69%, P = 0.04) and longer survival (median: 141 versus 80.5 weeks, P = 0.007) compared with those with ratios more than median. For patients with UC, values of either B2:BX or PK*B2:BX below the median had an inferior response rate to induction therapy (35 versus 78%, P = 0.0006) and inferior survival outcomes (median survival: 11 versus 53 weeks, P = 0.00002). Interestingly, FIPC and UC patients with antiapoptotic ratios (defined as B2:BX or PK*B2:BX more than median) had identical response rates and survival outcomes. In multivariate analyses, the compound variables of cytogenetics and B2:BX, or PK*B2:BX were independent predictors of survival. These results suggest that expression levels of proteins that affect the functional status of BCL2 modify the prognostic impact of BCL2 and suggest that the role of apoptosis in different cases of AML varies independently in the different cytogenetic subgroups.
AB - Previously, we demonstrated that the level of BCL2 expression is prognostic in acute myelogenous leukemia (AML). High levels of BCL2 correlate with an adverse outcome when associated with favorable and intermediate prognosis cytogenetics (FIPC), whereas low levels portend an adverse outcome when associated with unfavorable cytogenetics (UC). Because BCL2 function can be modulated by dimerization with family members, like BAX, or by phosphorylation by protein kinase C α (PKCα), we hypothesize that the relative expression of these proteins in primary leukemic cells might alter the prognostic impact of BCL2 expression. We therefore measured BAX and PKCα protein levels in peripheral blood mononuclear cell lysates from 165 newly diagnosed AML patients and correlated the expression of these proteins with BCL2 expression, patient survival, and remission induction success. Expression levels of BAX and PKCα were normalized against a control cell line, K562. BAX and PKCα expression levels were heterogeneous and did not correlate with the percentage of blasts in the sample (R2 = 0.01 and <0.01). The median expression of both was similar across FAB groups but the range was greater for M4. A similar distribution of expression was observed in all cytogenetic groups, except that patients with inversion 16 demonstrated lower levels of BAX. Individually, neither PKCα nor BAX expression was prognostic of response to induction therapy or survival. A similar outcome was obtained when patients were stratified by cytogenetics into FIPC and UC groups. However, the ratio of either BCL2:BAX (B2:BX) or PKCα*B2:BX (PK*B2:BX) was highly prognostic. Patients with FIPC and a lower ratio (less than median) of either B2:BX or PK*B2:BX had a significantly higher remission induction rate (88 versus 69%, P = 0.04) and longer survival (median: 141 versus 80.5 weeks, P = 0.007) compared with those with ratios more than median. For patients with UC, values of either B2:BX or PK*B2:BX below the median had an inferior response rate to induction therapy (35 versus 78%, P = 0.0006) and inferior survival outcomes (median survival: 11 versus 53 weeks, P = 0.00002). Interestingly, FIPC and UC patients with antiapoptotic ratios (defined as B2:BX or PK*B2:BX more than median) had identical response rates and survival outcomes. In multivariate analyses, the compound variables of cytogenetics and B2:BX, or PK*B2:BX were independent predictors of survival. These results suggest that expression levels of proteins that affect the functional status of BCL2 modify the prognostic impact of BCL2 and suggest that the role of apoptosis in different cases of AML varies independently in the different cytogenetic subgroups.
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M3 - Article
C2 - 10778970
AN - SCOPUS:0033624762
SN - 1078-0432
VL - 6
SP - 1401
EP - 1409
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -