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

Author:

Bartaula-Brevik Sushma1ORCID,Leitch Calum2,Hernandez-Valladares Maria13456ORCID,Aasebø Elise134ORCID,Berven Frode S.34,Selheim Frode34,Brenner Annette K.1,Rye Kristin Paulsen1,Hagen Marie1,Reikvam Håkon17ORCID,McCormack Emmet2ORCID,Bruserud Øystein17,Tvedt Tor Henrik Anderson17

Affiliation:

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

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.

Funder

Kreftforeningen, the Norwegian Cancer Society

Research Council of Norway

Bergen Research Foundation

Publisher

MDPI AG

Subject

General Medicine

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