Blocking the APRIL circuit enhances acute myeloid leukemia cell chemosensitivity.
Resistance to chemotherapy-induced cell death represents a major obstacle in the treatment of acute myeloid leukemia. APRIL (A Proliferation Inducing Ligand) is a member of the tumor necrosis factor superfamily that plays a key role in normal B-cell development, while promoting survival and proliferation of malignant B cells. We investigated APRIL expression and activity in acute myeloid leukemia. We found that APRIL mRNA and protein, including the secreted form, are expressed in leukemic cells of patients with M0, M2 and M4 acute myeloid leukemia subtypes but not in normal hematopoietic progenitors. Retrovirus-mediated APRIL expression in normal hematopoietic progenitors confers resistance to chemotherapeutic drugs-induced apoptosis. Conversely, blocking APRIL function by recombinant soluble APRIL receptors increased chemotherapeutic drugs-induced cell adeath in acute myeloid leukemia cells. These results indicate that APRIL acts in an autocrine fashion to protect acute myeloid leukemia cells from drug-induced death and foresee a therapeutic potential of APRIL antagonists in the treatment of acute myeloid leukemia.
Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy.
Désirée
D
Bonci
Maria
M
Musumeci
Valeria
V
Coppola
Antonio
A
Addario
Concetta
C
Conticello
Michael
M
Hahne
Massimo
M
Gulisano
Francesco
F
Grignani
Ruggero
R
De Maria
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019898:Autocrine Communication; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13