BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia.
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 alpha (PKCalpha), 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 PKCalpha 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 PKCalpha were normalized against a control cell line, K562. BAX and PKCalpha 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 PKCalpha 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 PKCalpha*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.
Kornblau
S M
SM
Section of Molecular Hematology and Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, 77030-4095, USA. skornblau@mdacc.tmc.edu
Vu
H T
HT
Ruvolo
P
P
Estrov
Z
Z
O'Brien
S
S
Cortes
J
J
Kantarjian
H
H
Andreeff
M
M
May
W S
WS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western; D020732:Cytogenetic Analysis; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011379:Prognosis; D011493:Protein Kinase C / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012074:Remission Induction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C