  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.
