Management of chronic myeloid leukemia: Targets for molecular therapy

Targets for molecular therapy. Each target is numbered and marked with a red cross. 1. The Src homology 1 (SH1) or tyrosine kinase domain of Bcr-Abl: its activity may be inhibited by signal transduction inhibitors, such as imatinib mesylate or adaphostin. 2. The oligomerization (coiled-coil) domain of Bcr-Abl: deletion/mutation or blocking of this domain with peptides that prevent oligomerization renders Bcr-Abl nontransforming. 3. The nuclear export signal (NES) receptor: inhibition of this nuclear protein with leptomycin B combined with inactivation of Bcr-Abl with imatinib entraps Bcr-Abl in the nucleus; subsequent reactivation of nuclear Bcr-Abl by removal of imatinib leads to apoptosis. 4. Heat-shock protein 90 (Hsp90): Hsp90 functions as chaperone that maintains the stability of the Bcr-Abl protein; antagonists of Hsp90, such as geldanamycin, destabilize Bcr-Abl and promote its proteasomal degradation. 5. BCR-ABL mRNA: synthesis of the Bcr-Abl oncoprotein may be suppressed by inhibiting BCR-ABL mRNA by either antisense oligonucleotides, ribozymes, or DNAzymes. 6. The SH3 domains of the adapter proteins Grb2 or CrkL: synthetic peptides that bind to these domains “uncouple” Bcr-Abl from downstream signaling pathways. 7. Farnesyl transferase: inhibitors of farnesyl transferase suppress Ras signaling by preventing the attachment of a farnesyl group to Ras; farnesyl groups are essential for the normal functioning of Ras since they tether these G-proteins to the plasma membrane. 8. Mek (MAPK or ERK Kinase): Bcr-Abl constitutively activates the Ras-Raf-Mek-Erk pathway; Mek inhibitors may be useful for inhibiting this mitogenic cascade 9. Phosphatidinylinositol-3 (PI-3) kinase: PI-3 kinase associates with Bcr-Abl and undergoes activation as a result of tyrosine phosphorylation; PI-3 kinase cell signaling may be inhibited with compounds such as wortmannin or LY294002, resulting in apoptosis by activation of Bad (pro-apoptotic) via Akt and its dissociation from Bcl-X_L (anti-apoptotic). 10. Bcr-Abl junction-specific peptides used as a potential vaccine for CML patients: the aim is to stimulate an immune response mediated by T-lymphocytes.