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Article

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity

by
Sushma Bartaula-Brevik
1,†,
Calum Leitch
2,†,
Maria Hernandez-Valladares
1,3,4,5,6,
Elise Aasebø
1,3,4,
Frode S. Berven
3,4,
Frode Selheim
3,4,
Annette K. Brenner
1,
Kristin Paulsen Rye
1,
Marie Hagen
1,
Håkon Reikvam
1,7,
Emmet McCormack
2,
Øystein Bruserud
1,7,* and
Tor Henrik Anderson Tvedt
1,7
1
Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
2
Department of Clinical Science, Centre for Pharmacy, University of Bergen, 5015 Bergen, Norway
3
The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway
4
The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
5
Department of Physical Chemistry, University of Granada, Avenida de la Fuente Nueva S/N, 18071 Granada, Spain
6
Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
7
Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2023, 12(17), 5546; https://doi.org/10.3390/jcm12175546
Submission received: 10 July 2023 / Revised: 20 August 2023 / Accepted: 23 August 2023 / Published: 25 August 2023
(This article belongs to the Special Issue Recent Progress in Leukemia: Where Do We Stand?)
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Abstract

Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.
Keywords: acute myeloid leukemia; vacuolar ATPase; bafilomycin A1; concanamycin; proliferation; apoptosis; cytokine; casein kinase 2; toxicity acute myeloid leukemia; vacuolar ATPase; bafilomycin A1; concanamycin; proliferation; apoptosis; cytokine; casein kinase 2; toxicity

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MDPI and ACS Style

Bartaula-Brevik, S.; Leitch, C.; Hernandez-Valladares, M.; Aasebø, E.; Berven, F.S.; Selheim, F.; Brenner, A.K.; Rye, K.P.; Hagen, M.; Reikvam, H.; et al. Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity. J. Clin. Med. 2023, 12, 5546. https://doi.org/10.3390/jcm12175546

AMA Style

Bartaula-Brevik S, Leitch C, Hernandez-Valladares M, Aasebø E, Berven FS, Selheim F, Brenner AK, Rye KP, Hagen M, Reikvam H, et al. Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity. Journal of Clinical Medicine. 2023; 12(17):5546. https://doi.org/10.3390/jcm12175546

Chicago/Turabian Style

Bartaula-Brevik, Sushma, Calum Leitch, Maria Hernandez-Valladares, Elise Aasebø, Frode S. Berven, Frode Selheim, Annette K. Brenner, Kristin Paulsen Rye, Marie Hagen, Håkon Reikvam, and et al. 2023. "Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity" Journal of Clinical Medicine 12, no. 17: 5546. https://doi.org/10.3390/jcm12175546

APA Style

Bartaula-Brevik, S., Leitch, C., Hernandez-Valladares, M., Aasebø, E., Berven, F. S., Selheim, F., Brenner, A. K., Rye, K. P., Hagen, M., Reikvam, H., McCormack, E., Bruserud, Ø., & Tvedt, T. H. A. (2023). Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity. Journal of Clinical Medicine, 12(17), 5546. https://doi.org/10.3390/jcm12175546

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