title: Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker.
abstract: BCR-ABL is a key mediator in the pathogenesis of all cases of chronic myelogenous leukemia (CML) and a subset of precursor B-acute lymphoblastic leukemia (Ph+ALL). Previous animal and cell-based studies have shown that the expression of members of the Forkhead family of tumor suppressors, including FoxO3, is suppressed in BCR-ABL-expressing cells. Furthermore, it has been reported that the proteasomal degradation pathway plays an important role in suppression of FoxO expression in BCR-ABL-transformed cells. In this study, a patient diagnosed with Ph+ALL and refractory to standard therapies was treated with a proteasome inhibitor (bortezomib)-based chemotherapy regimen. This treatment resulted in complete hematologic, cytogenetic and molecular remission with excellent performance status for > 4 years since her initial diagnosis. FoxO3 was not detectable within the blasts of this patient at diagnosis and was 'rescued' following treatment with bortezomib therapy, leading to her recovery. As a next step, in the attempt to propose FoXO3 as a therapeutic target and a theranostic marker, we further validated FoxO3 expression in human bone marrow biopsy samples. Human core biopsy samples of Ph+ALL and Ph-negative-negative ALL, along with uninvolved controls, revealed that FoxO3 down-regulation was specific to Ph+ALL. This study provides support that FoxO3 is a good biomarker for BCR-ABL-mediated leukemogenesis. Additionally, proteasomal inhibition by bortezomib may be a promising therapeutic option in Philadelphia-positive ALL, where FoxO3 is downregulated.
authors.affiliation: Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston MA, USA. rdewar@bidmc.harvard.edu
authors.forename: Rajan
authors.initials: R
authors.lastname: Dewar
authors.forename: Sing-Tsung
authors.initials: ST
authors.lastname: Chen
authors.forename: Heather
authors.initials: H
authors.lastname: Yeckes-Rodin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Miller
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use*; D012074:Remission Induction; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011719:Pyrazines; D000069286:Bortezomib; D016044:Fusion Proteins, bcr-abl