Signal Transduction by the Philadelphia Chromosome-encoded BCR/ABL Oncoproteins: Therapeutic Implications for Chronic Myeloid Leukemia and Philadelphia-positive Acute Lymphoblastic Leukemia

Abstract

The Philadelphia chromosomes characteristic of chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (ALL) encode chimeric protein tyrosine kinases (PTKs) derived by fusion of the normal BCR and ABL genes. The oncogenic properties of these BCR/ABL oncoproteins are dependent on their elevated PTK activity and on their ability to interact with multiple signal transduction systems. Here we summarize some of the key pathways which are activated by normal receptors with PTK activity and which modulate cell proliferation and survival. Next, we review some of the biochemical pathways initiated by BCR/ABL oncoproteins and discuss their possible relevance to the leukemic phenotype. We finally review experimental approaches designed to suppress signalling by BCR/ABL oncoproteins and discuss their potential therapeutic applications.

Keywords:

• Philadelphia chromosome
• chronic myeloid leukemia
• protein tyrosine kinase
• adaptor protein