Proteasome inhibition causes regression of leukemia and abrogates BCR-ABL-induced evasion of apoptosis in part through regulation of forkhead tumor suppressors.
BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. Here, we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the forkhead family of tumor suppressors in vitro, in an in vivo animal model, and in samples from patients with BCR-ABL-positive CML or ALL. As several downstream mediators of BCR-ABL are regulated by the proteasome degradation pathway, we also show that inhibition of this pathway, using bortezomib, causes regression of CML-like disease. Bortezomib treatment led to inhibition of BCR-ABL-induced suppression of FoxO proteins and their proapoptotic targets, tumor necrosis factor-related apoptosis-inducing ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. We additionally show sensitivity of imatinib-resistant BCR-ABL T315I cells to bortezomib. Our data delineate the involvement of FoxO proteins in BCR-ABL-induced evasion of apoptosis and provide evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL-induced leukemia.
Jagani
Zainab
Z
Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Song
Keli
K
Kutok
Jeffery L
JL
Dewar
M Rajan
MR
Melet
Armelle
A
Santos
Tanya
T
Grassian
Alexandra
A
Ghaffari
Saghi
S
Wu
Catherine
C
Yeckes-Rodin
Heather
H
Rodin
Heather Yeckes
HY
Ren
Ruibao
R
Miller
Kenneth
K
Khosravi-Far
Roya
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001549:Benzamides; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism* / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology; D012074:Remission Induction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D051858:Forkhead Transcription Factors; D010879:Piperazines; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl