Since the introduction of imatinibtreatment for CMLthere has been increasing concern about extramedullary relapse (EMR) despite favorable response in the bone-marrow.
We postulated that imatinib induces molecular changes associatedwith enhanced migration and adhesion abilitiesenabling CML cells to inhabitextramedullary sites.Pyk2 is a tyrosine kinase localized to focal adhesion sites that is implicated in mediating cell adhesion and motility.We have recently shown an increase in migration, adhesion and invasion capabilities of NB4 (APL) cells following treatment with the targeted therapy ATRA routinely used for treating APL patients and identified Pyk2 as one of the major mediators of these processes.
In agreement with our previous report, we reveal that CML cell-lines and patient cells demonstrate a 2-3-fold elevation of Pyk2 mRNA and protein expression when exposed to imatinib. This increase in pyk2 expression subsequently led to enhanced adhesion (5-fold) migration (7-fold)and invasion (2-fold)capabilities of K562 cells.
Interestingly, the non-adherent population was 50% more sensitive to imatinib treatment, suggesting thatthe acquired adhesive phenotype may grant the cells a certain level of resistant.Inhibition of Pyk2 resulted in a 2-fold and 5-fold reduction of K562 cell adhesion and migration abilities following imatinib treatment.These results correlate with ourpreviously published data regarding NB4 cells exposed to ATRA.
We suggest an active role for the novel targeted therapies in the occurrence of EMR in hematological malignancies. Agents such as ATRA and imatinib could induce expression of molecules that promote migration and extravasation of leukemic cells enabling their adhesion to extramedullary sites forming a reservoir of cells that could later proliferate and result in an EMR. Since the use of targeted therapies is broadening, we should be aware that alongside their therapeutic effect they may obtain a detrimental nature with respect to extramedullary manifestation in hematological malignancies.
