Journal
BLOOD ADVANCES
Volume 6, Issue 2, Pages 652-663Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2021005300
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Funding
- India Alliance Wellcome-Department of Biotechnology in India (DBT) [IA/CPHS/18/1/503930]
- Department of Biotechnology-Centre of Excellence (DBT-COE) [BT/COE/34/SP13432/2015]
- Department of Science and Technology-Science and Engineering Research Board (DST-SERB) (New Delhi, India) [CRG/2019/001214]
- senior fellowship program of India Alliance Wellcome-DBT (New Delhi, India) [IA/CPHS/18/1/503930]
- Council for Scientific and Industrial Research (New Delhi, India)
- DBT, Government of India
- Department of Science and Technology Fund for Improvement of Science and Technology (S&T) Infrastructure [SR/FST/LSI-649/2015]
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This study investigates the resistance mechanisms of acute promyelocytic leukemia (APL) to arsenic trioxide (ATO) treatment. The researchers generated ATO-resistant cell lines and found significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and PML-RARA mutation compared to sensitive cell lines. Gene expression profiling revealed dysregulation of metabolic pathways in ATO-resistant APL cell lines.
Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain most disease recurrence seen in the clinic. We have generated stable ATO-resistant promyelocytic cell lines that are less sensitive to all-trans retinoic acid (ATRA) and the combination of ATO and ATRA compared with the sensitive cell line. Characterization of these resistant cell lines that were generated in-house showed significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) mutation. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in these ATO-resistant APL cell lines. Glycolytic inhibition by 2-deoxyglucose (2-DG) was sufficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell line. 2-DG was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO-resistant cell lines. In contrast, the resistant cell lines were significantly affected by compounds targeting mitochondrial respiration when combined with ATO, irrespective of the ATO resistance-conferring genetic mutations or the pattern of their anti-apoptotic protein dependency. Our data demonstrate that combining mitocans with ATO can overcome ATO resistance. We also show that this combination has potential for treating non-M3 acute myeloid leukemia (AML) and relapsed APL. The translation of this approach in the clinic needs to be explored further.
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