A closer look at specific therapeutic strategies in leukemia.
Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins, such as PML-RARalpha and AML1-ETO, have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could represent an important target for new therapeutic agents. On the other hand, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways involved normally in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we present a closer look at our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction. In addition, the application of low molecular weight drugs for human leukemia treatment based in this knowledge results in durable clinical remission and acceptable risk of toxic effects that should increase the cure rate. We hope that this review will provide timely information to the readers.
Martinez-Mancilla
M
M
Depto de Genética y Biología Molecular, CINVESTAV-IPN, Av. Instituto Politécnico Nacional No 2508, Col San Pedro Zacatenco, 07360 México D. F.
Zafra
G
G
Reynoso-Gómez
E
E
Martinez-Avalos
A
A
Rivera-Luna
R
R
Gariglio
P
P
D000970:Antineoplastic Agents / Q000627:therapeutic use; D042002:Chromatin Assembly and Disassembly; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors