ROLE OF NOTCH AND JAK/STAT SIGNALING PATHWAYS IN ACUTE MEGAKARYOBLASTIC LEUKEMIA

Abstract

CHILDREN OF DOWN SYNDROME (DS), THE MOST COMMON CONGENITAL DISEASE, ARE AT HIGH RISK OF DEVELOPING ACUTE MEGAKARYOBLASTIC LEUKEMIA (AMKL). THE PREVALENCE OF AMKL IN SINGAPORE AND MALAYSIA IS STRIKINGLY HIGH AS COMPARED TO THE WORLDWIDE POPULATIONS, AND ITS PROGNOSIS IS UNFAVORABLE. IN ADDITION, THE MECHANISTIC BASIS FOR AMKL REMAINS ELUSIVE. TO DISCOVER CURRENTLY UNKNOWN GENETIC ALTERATIONS ASSOCIATED WITH AMKL, AN AMKL MOUSE MODEL WAS DEVELOPED EMPLOYING RETROVIRAL INSERTIONAL MUTAGENESIS (RIM) AND TARGETED DEEP SEQUENCING STRATEGY IN AMKL PATIENT SAMPLES AND CELL LINES. I HAVE READILY IDENTIFIED GENETIC MUTATIONS AND POTENTIAL AMKL GENES, WHICH ARE CLASSIFIED INTO TWO SIGNALING PATHWAYS, NAMELY JAK-STAT AND NOTCH PATHWAYS. IN VITRO CELL BASED DRUG TESTING ASSAYS USING NOTCH AGONIST AND JAK INHIBITOR SIGNIFICANTLY SUPPRESSED AMKL CELL PROLIFERATION BY INDUCING APOPTOSIS. THEREFORE, WE PROPOSE THAT JAK-STAT ACTIVATION AND NOTCH INACTIVATION DUE TO RESPECTIVE GENETIC MUTATION APPEAR TO