STAT signaling in the pathogenesis and treatment of myeloid malignancies

Abstract

STAT transcription factors play a critical role in mediating the effects of cytokines on myeloid cells. As STAT target genes control key processes such as survival, proliferation and self-renewal, it is not surprising that constitutive activation of STATs, particularly STAT3 and STAT5, are common events in many myeloid tumors. STATs are activated both by mutant tyrosine kinases as well as other pathogenic events, and continued activation of STATs is common in the setting of resistance to kinase inhibitors. Thus, the targeting of STATs, alone or in combination with other drugs, will likely have increasing importance for cancer therapy.

Keywords: STATs; leukemia; myeloproliferative neoplasms; oncology; therapy; transcription factors.

Figure 1. STAT transcription factors, primarily STAT3 and STAT5, are activated in myeloid malignancies through a variety of mechanisms, including autocrine and paracrine growth factors, mutated receptors and kinases and decreased activity of negative regulators including phosphatases and SOCS proteins. Activated dimers bind to the regulatory region of target genes, recruit co-activators and modulate transcription of key target genes.

Figure 2. In myeloid leukemias and myeloproliferative neoplasms, a variety of mutations can lead to the activation of tyrosine kinases that can phosphorylate STATs, particularly STAT5 and STAT3. These STATs then drive the transcriptional activation of genes regulating survival, proliferation, self-renewal and other phenotypes characteristic of these diseases.

Figure 3. The activation of STATs in cancer cells can be blocked by modulating targets resulting in loss of STAT phosphorylation. This includes inhibition of receptors and their ligands, inhibition of activated kinases (both mutated and unmutated) or activation of negative regulators such as phosphatases and SOCS proteins.

Figure 4. In addition to inhibiting kinases, STATs can be targeted directly by blocking their ability to form activated dimers, translocate into the nucleus, bind DNA or recruit co-activators.