Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML).
The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and Bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow cytometry using an anti-bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated with French-American-British (FAB) M0-M1 classes (P =.000 01) and CD34 more than 20% (P <.000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r = -.40, P <.000 001 and r = -.29, P =.000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P =.0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels (79% versus 45%; P =.000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P =.000 01 and =.019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 ratio was significantly associated both with a higher CR rate (86% versus 42%; P <.000 01) and a longer OS (P =.0016). The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel proapoptotic molecules in order to circumvent chemoresistance.
Del Poeta
Giovanni
G
Cattedra e Divisione Ematologia, Università Tor Vergata, Ospedale S. Eugenio, Roma, Italy. g.delpoeta@tin.it
Venditti
Adriano
A
Del Principe
Maria Ilaria
MI
Maurillo
Luca
L
Buccisano
Francesco
F
Tamburini
Anna
A
Cox
Maria Christina
MC
Franchi
Annibale
A
Bruno
Antonio
A
Mazzone
Carla
C
Panetta
Paola
P
Suppo
Giovanna
G
Masi
Mario
M
Amadori
Sergio
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology*; D008875:Middle Aged; D008928:Mitochondria / Q000737:chemistry; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D012044:Regression Analysis; D012074:Remission Induction; D015996:Survival Rate; D051028:bcl-2-Associated X Protein
D018952:Antigens, CD34; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019009:Proto-Oncogene Proteins c-kit