Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker.

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.