ABSTRACT
Th e recent WHO classifi cation of leukemia is on a clinico-pathologic-genetic basis and incorporates two distinct classes of genetic events: those that cause failure of diff erentiation/apoptosis and those that promote proliferation. Th is partially applies to myeloproliferative neoplasms (MPNs) of which chronic myelogenous leukemia is a prototype. In chronic myelogenous leukemia (CML), the ‘breakpoint cluster region’-‘Abelson’ (BCR-ABL) oncoprotein responsible for its leukemogenic properties can be targeted with tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec, STI-571). While Tyrosine kinase inhibitors (TKIs) are shown to induce apoptosis by abrogating BCR-ABL driven responses, therapeutic nonresponsiveness to TKIs or the inability of a small population of ‘residual leukemic stem cells’ to undergo apoptosis results in failure of achieving a cure in a major subset of patients with CML. Th is demands detailed investigations of additional eff ector pathways that can be targeted. A multitude of signaling pathways are
triggered by BCR-ABL and many of these result in inhibition of apoptosis. Th ese include Ras, PI3K/Akt, JAK/STAT and NF-kB. A few secondary pathways such as proteasomal degradation of cellular proteins are also possibly eff ective in inhibiting apoptosis in CML. For instance, proteasomal mediated cytoplasmic FoxO3a degradation results in inhibition of apoptosis and increased cell survival in CML. Proteasomal inhibition, through alternative therapeutic agents, such as bortezomib, may be useful as an adjunct in TKI resistant CML and perhaps may be eff ective at the leukemic stem cell level. Th is chapter discusses recent advances in understanding primary and secondary pathways downstream of BCR-ABL signaling with a focus on alternative approaches to CML therapy.
