The Important Role of STAT3 in Chronic Lymphocytic Leukaemia Biology

Abstract

Background:Signal transducer and activator of transcription (STAT) proteins are cytoplasmic transcription factors that transmit the signal of cytokines, hormones and growth factors. STAT proteins control fundamental cellular processes including survival, proliferation and differentiation. Inappropriate activation of STATs might contribute to cellular transformation and leukaemogenesis. About 70% of all solid and haematological tumours exhibit aberrant STAT3 expression and/ or activation, highlighting its essential role in tumourigenesis. Aberrant STAT3 activation has been found in several solid tumours and haematologic malignancies. Importantly, constitutive activation of STAT proteins has been found in several leukaemias including acute myeloid leukaemia, acute promyelocytic leukaemia, acute lymphoblastic leukaemia, chronic myeloid leukaemia and chronic lymphocytic leukaemia (CLL). Constitutively activated STAT3 plays an important role in CLL bio logy. CLL cells harbour constitutive phosphorylation on S727 and acetylation on K685 and transient phosphorylation on Y705 residues. Moreover, STAT3 messenger RNA expression is significantly higher in CLL cells compared to healthy B-lymphocytes. Interestingly, STAT3 inhibition was disclosed as an important by-product of ibrutinib treatment in CLL patients. Purpose: The purpose of this review is to describe the consequences of STAT3 dysregulation in CLL cells. Here, we discuss aberrantly modified processes by STAT3 activation in CLL cells such as proliferation, apoptosis, B cell receptor signalling, cytokine secretion, immune checkpoint regulation, microRNA regulation, free fatty acid metabolism and electron transport chain in the mitochondria. SouhrnVýchodiska: Proteiny STAT (signal transducer and activator of transcription) jsou cytoplazmatické transkripční faktory, které přenášejí signál cytokinů, hormonů a růstových faktorů. Proteiny STAT kontrolují základní buněčné procesy vč. přežití, proliferace a diferenciace. Nadměrná aktivace proteinů STAT může přispět k transformaci buněk a vzniku leukemie. Okolo 70 % všech solidních a hematologických nádorů vykazuje aberantní expresi a/ nebo aktivaci STAT3, což dokumentuje zásadní roli STAT3 v tumorigenezi. Aberantní aktivace STAT3 byla popsána u několika solidních nádorů a hematologických malignit. Důležité je, že konstitutivní aktivace proteinů STAT byla detekována u několika typů leukemie vč. akutní myeloidní leukemie, akutní promyelocytární leukemie, akutní lymfoblastické leukemie, chronické myeloidní leukemie a chronické lymfocytární leukemie (CLL). Konstitutivně aktivovaný STAT3 hraje důležitou roli v bio logii CLL. Buňky CLL jsou konstitutivně fosforylované na S727 a acetylované na K685, navíc může dojít i k fosforylaci na Y705. Exprese mediátorové RNA STAT3 je výrazně vyšší v buňkách CLL ve srovnání se zdravými B lymfocyty. Zajímavé je, že inhibice STAT3 byla popsána jako důležitý vedlejší produkt léčby ibrutinibem u pacientů s CLL. Cíl: Účelem tohoto přehledu je popsat důsledky deregulace STAT3 u buněk CLL. V práci j...

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