Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia

Abstract

We have demonstrated that constitutive signal transducer and activator of transcription (STAT) 3 activity, observed in approximately 50% of acute myeloid leukemia (AML) cases, is associated with adverse treatment outcome. Constitutive STAT3 activation may result from the expression of oncogenic protein tyrosine kinases or from autocrine stimulation by hematopoietic growth factors. These causes are generally neither necessary nor sufficient for leukemogenesis; additional transforming events or growth stimulatory processes are needed. Here we review the literature addressing epigenetic regulation as a mechanism controlling STAT3 signaling in AML. A better understanding of mechanisms of dysregulation of STAT signaling pathways may serve as a basis for designing novel therapeutic strategies that target these pathways in leukemia cells.

Figure 1

Regulation of the JAK-STAT signaling pathway. Ligand-induced receptor oligomerization activates JAKs which subsequently phosphorylate tyrosine residues on the cytoplasmic portion of the receptor. The quiescent STAT monomers are then recruited to the activated receptor complex via the interaction of the SH2 domains with phosphotyrosine docking sites. STATs are phosphorylated by the JAKs on a conserved tyrosine residue in the c-terminal domain to form STAT homo- or heterodimers. STATs dissociate from the receptor after the dimerization and translocate into the nucleus. In the nucleus, STATs bind to specific response elements and induce gene transcription. Signaling is inhibited by four different mechanisms: SHP dephosphorylates activated JAKs and STATs, SOCS inhibits JAKs and STATs, and PIAS and SLIM inhibit transcriptional activities.

Figure 2

Modular structure of the STAT inhibitors. SH2, Src homology 2; SB, SOCS Box; KIR, kinase inhibitory region; SUMO, small ubiquitin-related modifier; SAP, represents three proteins SAFA/B, ACINUS, PIAS; Ring, zinc binding domain; S/T, serine/threonine-rich region; PDZ, represents three proteins PSD95, Drosophila tumor suppressor disc large, and epithelial tight junction protein zona occludens-1; LIM, represents three proteins LIN-11, Isl1, and MEC-3.