Deregulation of calcium homeostasis in Bcr-Abl-dependent chronic myeloid leukemia

// Helene Cabanas 1 , Thomas Harnois 1 , Christophe Magaud 2 , Laetitia Cousin 1 , Bruno Constantin 1 , Nicolas Bourmeyster 1 and Nadine Deliot 1 1 Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM) ERL CNRS 7368, Equipe Calcium et Microenvironnement des Cellules Souches (CMCS), Universite de Poitiers, 86073 Poitiers, France 2 Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM) ERL CNRS 7368, Equipe Transferts Ioniques et Rythmicite Cardiaque (TIRC), Universite de Poitiers, 86073 Poitiers, France Correspondence to: Bruno Constantin, email: bruno.constantin@univ-poitiers.fr Keywords: chronic myeloid leukemia; leukemogenesis; calcium homeostasis; STIM1/Orai1/TRPC1; store-operated calcium entry Received: September 29, 2017      Accepted: April 03, 2018      Published: May 29, 2018 ABSTRACT Background: Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the bcr-abl chimeric oncogene, encoding a 210 kDa protein with constitutive tyrosine kinase activity. In spite of the efficiency of tyrosine kinase inhibitors (TKI; Imatinib), other strategies are explored to eliminate CML leukemia stem cells, such as calcium pathways. Results: In this work, we showed that Store-Operated Calcium Entry (SOCE) and thrombin induced calcium influx were decreased in Bcr-Abl expressing 32d cells (32d-p210). The 32d-p210 cells showed modified Orai1/STIM1 ratio and reduced TRPC1 expression that could explain SOCE reduction. Decrease in SOCE and thrombin induced calcium entry was associated to reduced Nuclear Factor of Activated T cells (NFAT) nucleus translocation in 32d-p210 cells. We demonstrated that SOCE blockers enhanced cell mobility of 32d-p210 cells and reduced the proliferation rate in both 32d cell lines. TKI treatment slightly reduced the thrombin-induced response, but imatinib restored SOCE to the wild type level. Bcr-Abl is also known to deregulate Protein Kinase C (PKC), which was described to modulate calcium entries. We showed that PKC enhances SOCE and thrombin induced calcium entries in control cells while this effect is lost in Bcr-Abl-expressing cells. Conclusion: The tyrosine kinase activity seems to regulate calcium entries probably not directly but through a global cellular reorganization involving a PKC pathway. Altogether, calcium entries are deregulated in Bcr-Abl-expressing cells and could represent an interesting therapeutic target in combination with TKI.