Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity Bartaula-Brevik, Sushma Hernández Valladares, María del Carmen Acute myeloid leukemia Vacuolar ATPase Bafilomycin A1 Concanamycin Proliferation Apoptosis Cytokine Casein kinase 2 Toxicity This work was supported by Kreftforeningen, the Norwegian Cancer Society (grant no. 100933). The Genomics Core Facility (GCF) is supported in part by major grants from the Research Council of Norway (grant no. 245979/F50) and Bergen Research Foundation. The GCF at the University of Bergen, which is part of the NorSeq consortium, provided support in ChIP-Seq bioinformatics analysis. Supplementary Materials: The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/jcm12175546/s1 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. 2023-10-24T07:22:27Z 2023-10-24T07:22:27Z 2023-08-25 info:eu-repo/semantics/article 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] https://hdl.handle.net/10481/85189 10.3390/jcm12175546 eng http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Atribución 4.0 Internacional MDPI