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
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