JAK/STATSignalling and Haematological Malignancies

Abstract

AbstractA major focus of investigation and drug screening efforts started with the discovery of JAK2V617F as a major driver of the BCR‐ABL‐negative myeloproliferative neoplasms (MPNs). An acquired somatic mutation,JAK2V617F, drives 65% of MPNs. Further studies established that these diseases almost always exhibit mutations leading to persistent JAK2‐STAT5 activation. Sequencing of the four mammalianJAKs(Janus kinases) (JAK1,JAK2,JAK3andTYK2) and of the seven STATs (signal transducers and activators of transcriptions) in a variety of cancers identified the pathologic activation of these JAKs and STATs, by mutations in the genes themselves or in upstream or downstream regulators as significant contributors to several haematological and solid malignancies. The development of JAK2, JAK1, JAK3 and TYK2 kinase inhibitors is unfolding with JAK2, JAK1 and JAK3 inhibitors being approved in certain conditions. Altogether, the JAK/STAT pathway became a new gold mine for discovery and therapy in haematological cancers.Key ConceptsThe JAK/STAT pathway has a central role in cytokine signalling in normal haematopoiesis.The JAK/STAT pathway is frequently pathologically activated by several mechanisms in many types of haematological malignancies.The JAK/STAT pathway can be targeted by small molecules.The JAK/STAT pathway can be pathologically activated by down‐modulation of negative regulators such as phosphatases.Constitutive STAT activation in blood cancers can be the result of several activated kinases, not only JAKs.JAK2 activation is the main mechanismresponsible of the poorprognosis of mostpediatric B‐cell acute lymphoblasticleukemia.