Deregulation of calcium homeostasis in Bcr-Abl-dependent chronic myeloid leukemia
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Hélène Cabanas1, Thomas Harnois1, Christophe Magaud2, Laëtitia Cousin1, Bruno Constantin1, Nicolas Bourmeyster1 and Nadine Déliot1
1Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM) ERL CNRS 7368, Equipe Calcium et Microenvironnement des Cellules Souches (CMCS), Université de Poitiers, 86073 Poitiers, France
2Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM) ERL CNRS 7368, Equipe Transferts Ioniques et Rythmicité Cardiaque (TIRC), Université de Poitiers, 86073 Poitiers, France
Bruno Constantin, email: firstname.lastname@example.org
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
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.
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