Acute myeloid leukemia: therapeutic impact of epigenetic drugs.
Acute myeloid leukemia (AML) is not a single disease but a group of malignancies in which the clonal expansion of various types of hematopoietic precursor cells in the bone marrow leads to perturbation of the delicate balance between self-renewal and differentiation that is characteristic of normal hematopoiesis. An increasing number of genetic aberrations, such as chromosomal translocations that alter the function of transcription regulatory factors, has been identified as the cause of AML and shown to act by deregulating gene programming at both the genetic and epigenetic level. While the genetic aberrations occurring in acute myeloid leukemia are fairly well understood, we have only recently become aware of the epigenetic deregulation associated with leukemia, in particular with myeloid leukemias. The deposition of epigenetic "marks" on chromatin - post-translational modifications of nucleosomal proteins and methylation of particular DNA sequences - is accomplished by enzymes, which are often embedded in multi-subunit "machineries" that have acquired aberrant functionalities during leukemogenesis. These enzymes are targets for so-called "epi-drugs". Indeed, recent results indicate that epi-drugs may constitute an entirely novel type of anti-cancer drugs with unanticipated potential. Proof-of-principle comes from studies with histone deacetylase inhibitors, promising novel anti-cancer drugs. In this review we focus on the epigenetic mechanisms associated with acute myeloid leukemogenesis and discuss the therapeutic potential of epigenetic modulators such as histone deacetylase and DNA methyltransferase inhibitors.
Altucci
Lucia
L
Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli (S.U.N.), Naples, Italy. lucia.altuccii@unina2.it
Clarke
Nicole
N
Nebbioso
Angela
A
Scognamiglio
Annamaria
A
Gronemeyer
Hinrich
H
D000107:Acetylation; D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors