Abstract 78P
Background
Breakpoint cluster region-Abelson (BCR:ABL1) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+ B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B-ALL. Dysregulation of redox homeostasis and reliance on the thioredoxin (TXN) antioxidant system has been previously shown in B-ALL. Herein, we investigated the role of peroxiredoxin-1 (PRDX1), an enzyme responsible for the scavenging of hydrogen peroxide, in Ph+ myeloid and lymphoid leukemia.
Methods
PRDX1 knockout and apoptotic proteins were assessed by immunoblotting. The numbers of viable BV173 (lymphoid) and K562 (myeloid) cells were evaluated by light microscope counting after discriminating dead cells with Trypan Blue staining. Cell cycle and proliferation were assessed with MUSE and Click-iT EdU tests, respectively. The viability of K562 and BV173 knockouts treated with TKIs was assessed with propidium iodide staining and flow cytometry.
Results
PRDX1 knockout reduced the numbers of viable BV173 cells grown in vitro, but did not affect the numbers of K562 cells. The addition of hydrogen peroxide scavenges to the culture medium restored the viability of BV173 cells. We observed no significant differences in cell proliferation or in cell cycle fractions in BV173sgPRDX1 cells. Notably, in contrast to the myeloid K562 cell line, lymphoid B-ALL cells lacking PRDX1 were much more sensitive to three tested TKIs: imatinib, dasatinib, and ponatinib.
Conclusions
The results reveal that the important role of PRDX1 for Ph+ leukemic cell viability and sensitivity to TKIs is restricted to lymphoid leukemias. The observed reduced numbers of PRDX1 knockout cells were not the effect of an altered cell cycle or proliferation but most likely due to increased apoptosis. These findings are part of a larger ongoing in vitro and in vivo study examining the sensitization of Ph+ lymphoid leukemia to TKIs through inhibition of the thioredoxin system and PRDX1.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Medical University of Warsaw.
Funding
SONATA BIS 2015/18/E/NZ5/00723 grant funded by the National Science Centre, entitled “Novel pro-oxidative strategies in the treatment of B cell acute lymphoblastic leukemia”.
Disclosure
All authors have declared no conflicts of interest.
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