טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentSchragenheim Rozales Kinneret
SubjectThe Role and Significance of Signal Transduction Pathways
in Response to Busulfan in AML cells
DepartmentDepartment of Medicine
Supervisors Dr. Yishai Ofran
Dr. Igal Louria-Hayon
Full Thesis textFull thesis text - English Version


Abstract

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Hematopoietic stem cell transplantation (HSCT) is effective and improve cure rate in high and intermediate risk AML patients. Conditioning prior to HSCT is essential for its success and Busulfan is one of the most common agents in use for

conditioning.

Extracellular signal-regulated kinase (ERK) cascade is one of the major investigated cascades since its  components are frequently mutated or constitutively activated in different type of cancer. The role of ERK activation in cell death following chemotherapy exposure remains controversial. In some studies, the ERK activation is associated with resistance to chemotherapy stress, while in other studies, the ERK activation is involved in apoptotic cell death. The present research was conducted to examine the role of ERK activation in Busulfan-induced cell death of AML cell lines (U937 and HL-60) and in primary AML Human blasts. Busulfan resulted in a time- and dose-dependent cell death, which was largely attributed to apoptosis. We have revealed that Busulfan treatment caused marked sustained activation of ERK leading to apoptosis. The ERK activation and AML cells death induced by Busulfan was prevented by U0126, an inhibitor of MEK1/2 in kinase upstream to ERK. Moreover, in cells derived from human patients, the response to Busulfan treatment was ERK dependent.

Taken together, these findings suggest that RAS/RAF/ERK signaling pathway plays active key role in mediating Busulfan-induced apoptosis of AML Human cell lines and in AML primary Human blasts.