How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms?

Abstract

A decade on from the discovery of the JAK2V617F mutation in the majority of patients with myeloproliferative neoplasms (MPNs), JAK2V617F is now firmly installed in the hematology curriculum of medical students and the diagnostic-testing algorithm of clinicians. Furthermore, the oral JAK1/JAK2 inhibitor ruxolitinib, rationally designed to target activated JAK2 signaling in MPN, has been approved by the Food and Drug Administration (FDA) of the United States for the past 3 years for the treatment of intermediate-and advanced-phase myelofibrosis. Notwithstanding this, JAK2V617F continues to stimulate the MPN research community and novel insights into understanding the mechanisms by which JAK2V617F contributes to the pathogenesis of MPN are continually emerging. In this chapter, we focus on recent advances in 4 main areas: (1) the molecular processes coopted by JAK2V617F to induce MPN, (2) the role that JAK2V617F plays in phenotypic diversity in MPN, (3) the functional impact of JAK2V617F on hematopoietic stem cells, and (4) therapeutic strategies to target JAK2V617F. Although great strides have been made, significant deficits still exist in our understanding of the precise mechanisms by which JAK2V617F-mutant hematopoietic stem cells emerge and persist to engender clonal hematopoiesis in MPN and in developing strategies to preferentially target the JAK2V617F-mutant clone therapeutically. Critically, although myelofibrosis remains arguably the greatest clinical challenge in JAK2V617F-mediated MPN, the current understanding of myelofibrosis-specific disease biology remains quite rudimentary. Therefore, many important biological questions pertaining to JAK2V617F will continue to engage and challenge the MPN research community in the coming decade. Learning Objective• To understand the role played by the JAK2V617F mutation in the development of MPNs: specifically, to outline its role in perturbing signal transduction, engendering distinct clinical disease phenotypes, altering hematopoietic stem cell function, and serving as a rational therapeutic target in MPN

Polycythemia Vera: New Diagnostic Concept and Its Types

“…Подтверждением данной молеку-лярной модели активации рецептора JAK2 является факт цитокиннезависимой активации рецептора в результате мутации (рис. 1, справа) [11,12].…”

Polycythemia Vera: Literature Review and Own Data

“…1. Структура молекулы и схема активации JAK2 [12]. Доменная структура JAK2: JAK2 состоит из тирозинкиназного (JH1), псевдокиназного (JH2) доменов и SH2, FERM.…”

“…1. The structure of the molecule and JAK2 activation scheme [12]. Domain structure of JAK2: JAK2 consists of tyrosine kinase (JH1), pseudokinase (JH2), SH2, and FERM domains.…”

New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape

“…Janus kinases (JAK1, JAK2, JAK3 and TYK2) mediate cytokine signaling via downstream activation of the STAT (signal transducers and activators of transcription) family of transcriptional regulators(12). Activated STATs promote transcription of genes that regulate multiple cellular functions, including proliferation, apoptosis, migration and differentiation(13).…”

“…JAK2 is critical role for hematopoiesis and mediates Epo, GM-CSF, thrombopoietin, growth hormone, leptin, IL-3 and IL-5 signaling(14, 15). Ligand binding induces conformational changes to cytokine receptors that results in activation of JAKs, which phosphorylate tyrosine residues on the intracellular receptor domain(12). These residues recruit downstream effectors bearing Src homology-2 or phosphotyrosine-binding domains, which leads to activation of STAT, Ras/MAPK and PI3K/AKT signaling pathways(12).…”