Abstract
Summary: The potential functional role of PDPK FA in various types of human leukemia cells was explored by investigating the effects of partial inhibition of this kinase on human acute lymphoblastic leukemia (Jurkat), acute myeloblastic leukemia (HL-60) and chronic myeloid leukemia (K562) cells by introducing antisense expression vector into these leukemia cells. In the stable antisense clones of Jurkat, HL-60 and K562 cells with specific suppression of PDPK FA exhibited growth retardation, poor clonogenic growth in soft agar and loss of serum independence. This is the first indication that suppression of PDPK FA is able to inhibit the malignant growth of various types of human leukemia cells. Furthermore, suppression of PDPK FA is also able to potentiate serum deprivation-induced apoptosis, suggesting an important role of this PDPK in regulating the resistance of leukemia cells to apoptosis. Moreover, suppression of PDPK FA is also able to dramatically enhance chemosensitivity of leukemia cells in response to various anticancer drugs. Mechanistic study further revealed that the enhanced chemosensitivity in these antisense clones is mainly due to potentiation of apoptotic induction. On the other hand, suppression of PDPK FA is also able to potentiate differentiation induction of leukemia cells in response to various differentiation-inducing agents. All the results presented in this thesis demonstrate the systemic functional role of PDPK FA in controlling malignant growth, apoptosis-, differentiation- and chemo-resistance of various types of human acute and chronic leukemia cells. Suppression of this multisubstrate/multifunctional PDPK may provide a new powerful strategy to serve as complementary therapy for human leukemia treatment.