Involvement of ORAI1/SOCE in Human AML Cell Lines and Primary Cells According to ABCB1 Activity, LSC Compartment and Potential Resistance to Ara-C Exposure

Int J Mol Sci. 2022 May 16;23(10):5555. doi: 10.3390/ijms23105555.

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with a high risk of relapse. This issue is associated with the development of mechanisms leading to drug resistance that are not yet fully understood. In this context, we previously showed the clinical significance of the ATP binding cassette subfamily B-member 1 (ABCB1) in AML patients, namely its association with stemness markers and an overall worth prognosis. Calcium signaling dysregulations affect numerous cellular functions and are associated with the development of the hallmarks of cancer. However, in AML, calcium-dependent signaling pathways remain poorly investigated. With this study, we show the involvement of the ORAI1 calcium channel in store-operated calcium entry (SOCE), the main calcium entry pathway in non-excitable cells, in two representative human AML cell lines (KG1 and U937) and in primary cells isolated from patients. Moreover, our data suggest that in these models, SOCE varies according to the differentiation status, ABCB1 activity level and leukemic stem cell (LSC) proportion. Finally, we present evidence that ORAI1 expression and SOCE amplitude are modulated during the establishment of an apoptosis resistance phenotype elicited by the chemotherapeutic drug Ara-C. Our results therefore suggest ORAI1/SOCE as potential markers of AML progression and drug resistance apparition.

Keywords: ABCB1; AML; Ara-C; NFAT; ORAI1; SOCE; calcium; leukemic stem cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Calcium / metabolism
  • Calcium Signaling
  • Cell Line
  • Cytarabine* / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • ORAI1 Protein / genetics
  • ORAI1 Protein / metabolism
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ORAI1 Protein
  • ORAI1 protein, human
  • Stromal Interaction Molecule 1
  • Cytarabine
  • Calcium

Grants and funding

This research was funded by grants from Contrat de Plan Etat-Région CPER Cancer 2015–2020, INSERM, CNRS, Ligue contre le cancer (Septentrion), Ligue nationale contre le cancer, Fondation ARC, the University of Lille and the Institut de Recherche sur le Cancer de Lille (IRCL). C.L. and M.-O.L. are financed by Lille Hospital and by the Hauts de France Region. F.A.S. is financed by the Institut de Recherche sur Le Cancer de Lille (IRCL).