STAT3 inhibitors: finding a home in lymphoma and leukemia.
The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is an active mediator of cytokine signaling in the pathogenesis of solid and hematologic malignancies. The seven-member STAT family is composed of latent cytoplasmic transcription factors that are activated by phosphorylation intertwined in a network with activation that ultimately leads to cell proliferation. An activated kinase enzyme phosphorylates one STAT factor or more, which shuttle to the nucleus to regulate gene expression, promoting cell survival. Somatic STAT3 mutations have been recently reported in large granular lymphocytic leukemia, aplastic anemia, and myelodysplastic syndrome. Furthermore, the relationship between BCL6 and STAT3 in diffuse large B-cell lymphomas, particularly on the activated B-cell subtype, needs to be further explored. The search for therapeutic STAT3 inhibitors that abrogate the JAK/STAT pathway is currently under way. Targeting the STAT pathway, which seems to be critical in tumorigenesis, is promising for multiple malignancies including lymphoma and leukemia. In this paper, we review mechanisms of action, failures, and successes of STAT3 inhibitors.
Hematology-Oncology, Banner, MD Anderson Cancer Center, Gilbert, Arizona, USA; Hematology-Oncology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; Departments of Investigational Cancer Therapeutics (Phase I Clinical Trials Program) and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Javier
J
Munoz
Navjot
N
Dhillon
Filip
F
Janku
Stephanie S
SS
Watowich
David S
DS
Hong
D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D010766:Phosphorylation; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D053612:Janus Kinases; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C084103:BCL6 protein, human; C508600:IL6 protein, human; C494086:STAT3 protein, human
IL6; JAK; Leukemia; Lymphoma; Phase I; STAT