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

TL;DR

This study investigates how Bcr-Abl oncogene deregulates calcium entry pathways in chronic myeloid leukemia cells, revealing potential new therapeutic targets beyond tyrosine kinase inhibitors.

Contribution

It uncovers the mechanisms of calcium homeostasis deregulation in Bcr-Abl-positive cells and explores how calcium pathways could be targeted alongside existing therapies.

Findings

Bcr-Abl reduces Store-Operated Calcium Entry (SOCE) and thrombin-induced calcium influx.

SOCE blockers increase cell mobility and decrease proliferation in leukemia cells.

Imatinib restores SOCE levels to normal in Bcr-Abl-expressing cells.

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.