Prognostic significance of BAD and AIF apoptotic pathways in diffuse large B-cell lymphoma.
BACKGROUND
To determine whether proapoptotic proteins were associated with clinicopathologic heterogeneity and influenced survival in patients with diffuse large B-cell lymphoma (DLBCL), we evaluated patterns of expression of the BCL-2 family member BAD, PP1alpha (the catalytic subunit of PP1 involved in activation of BAD), and apoptosis-inducing factor (AIF).


METHODS
We retrospectively analyzed 46 patients all treated with standard chemotherapy ([CHOP] cyclophosphamide/doxorubicin/vincristine/prednisone-like); of these, 16 received rituximab. Immunohistochemical analyses were performed from biopsy samples of nodal DLBCL that were performed at initial diagnosis. Normal reactive lymph nodes were used as controls.


RESULTS
BAD expression was found in 38 of 46 DLBCL cases and, though variable, was often strong. PP1alpha and AIF were detected in all tumors tested with a relative strong expression. Lower BAD expression was shown to be significantly associated with advanced clinical stages (Ann Arbor stage III + IV and International Prognostic Index intermediate-high to high; P = .006 and P = .0008, respectively). Moreover, BAD staining was positively correlated with BCL-2 (P = .022) and PP1alpha (P = .013) staining. Finally, high AIF expression proved to be predictive of a longer overall survival in non-rituximab-treated patients.


CONCLUSIONS
Our study shows for the first time in DLBCL that differential BAD expression might play a role in the development of the disease, possibly reflecting its function as a tumor suppressor. Furthermore, our data highlight the interest in targeting BAD phosphatases and AIF-mediated mitochondrial apoptosis for new therapeutic strategies.
Troutaud
Danielle
D
EA3842, Université de Limoges, France. danielle.troutaud@unilim.fr
Petit
Barbara
B
Bellanger
Cynthia
C
Marin
Benoît
B
Gourin-Chaury
Marie-Pierre
MP
Petit
Daniel
D
Olivrie
Agnès
A
Feuillard
Jean
J
Jauberteau
Marie-Odile
MO
Bordessoule
Dominique
D
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D001402:B-Lymphocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage / Q000627:therapeutic use; D011379:Prognosis; D000069283:Rituximab; D013267:Stilbenes; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051033:Apoptosis Inducing Factor; D013267:Stilbenes; C006711:benzoylamido-4'-aminostilbene-2,2'-disulfonate; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone