טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentYeheskely-Hayon Daniella
SubjectThe Role of BCR/ABL Oncogene in Resistance to Anti-Cancer
Drugs
DepartmentDepartment of Biology
Supervisor Professor Gera Eytan


Abstract

Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder associated with a specific chromosomal translocation. This translocation generates the BCR/ABL fusion gene that encodes the chimeric BCR-ABL protein. This fusion protein is a constitutively active tyrosine kinase that is identifiable throughout the course of the disease. CML cells exhibit multidrug resistance (MDR) and do not respond favorably to MDR-type drugs. The mechanisms of resistance and progression in CML are poorly understood.

In the present study, we show that the K562 cell-line derived from a chronic myelogenous leukemia patient exhibits ATP-dependent exclusion of the anticancer drug, doxorubicin. This exclusion was not modulated by inhibitors of either P-glycoprotein or MRP1 and is due to another yet unidentified resistance mechanism.

 Since the oncogene BCR/ABL is the causative agent and the hallmark of Ph-positive CML, the drug extrusion characteristic of these cells could be due to up-regulation by this oncogene. Our goal was to elucidate a possible causative link between BCR-ABL activity and multidrug resistance in CML.

            We have demonstrated that the specific inhibitors of protein kinases, the novel anticancer drug, STI571, and the tyrphostin, AG957, allowed for increased doxorubicin uptake into the K562 cells. Although the increase in doxorubicin cellular uptake exhibited a similar time course to apoptotic manifestations induced by these drugs, the two phenomena were independent. The consequence of these findings is that the combination of BCR-ABL inhibitors with antileukemic drugs is likely to have the added beneficiary effect of allowing drugs better access to the cells. Combination chemotherapy has the potential of avoiding the resistance to STI571 often observed in CML patients at the blast stage.