Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation

Abstract

Clonal alterations in hematopoietic cells occur during aging and are often associated with the establishment of a subclinical inflammatory environment. Several age-related conditions and diseases may be initiated or promoted by these alterations. JAK2 mutations are among the most frequently mutated genes in blood cells during aging. The most common mutation within the JAK2 gene is JAK2-V617F that leads to constitutive activation of the kinase and thereby aberrant engagement of downstream signaling pathways. JAK2 mutations can act as central drivers of myeloproliferative neoplasia, a pre-leukemic and age-related malignancy. Likewise, hyperactive JAK-signaling is a hallmark of immune diseases and critically influences inflammation, coagulation and thrombosis. In this review we aim to summarize the current knowledge on JAK2 in clonal hematopoiesis during aging, the role of JAK-signaling in inflammation and lymphocyte biology and JAK2 function in age-related diseases and malignant transformation.

Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon

“…However, how microglial cells are activated in the brain in Grna; Grnb-deficient animals remains elusive. Comparing the transcriptomes of wildtype and mutant microglial cells, we detected significant upregulation of numerous genes associated with MAPK and JAK/STAT signalling pathways, which are known to be involved in the regulation of pro-inflammatory cytokine production and microglial activation [66,67]. Similar results have been observed in the mouse brain, where GRN has been identified as a key regulator of inflammation, by tuning the expression of pro-inflammatory cytokines and complement factors during aging [38], thus suggesting that granulins directly adjust the levels of inflammatory cytokines to the corresponding aging state in both zebrafish and mammalian brains.…”

“…GO analysis (based on DAVID 6.8) revealed an enrichment in genes associated with inflammation, apoptosis, cell proliferation and extracellular matrix composition (Figure 1f,g; Table S1). Notably, many upregulated genes in mutant Mpeg1 + cells were associated with the tumor necrosis factor receptor, the MAPK and the JAK/STAT signalling pathways, which are involved in the induction of pro-inflammatory cytokine expression [66,67] (Figure 1f and Figure S3a). Furthermore, we identified numerous downregulated genes belonging to the PPAR signalling pathway, which has a role in counteracting the expression of pro-inflammatory cytokines [68] (Figure 1g and Figure S3a).…”

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

“…As aging in general is associated with increased inflammation, DNA damage, and senescence-associated secretory phenotype, with myeloid skewing in the hematopoietic compartment [104,105]; this likely provides an environment that selects for the expansion of genetic variants such as JAK2 V617F [9]. Consequently, age-related clonal hematopoiesis harboring somatic mutations frequently detected in hematologic malignancies is very common, if not inevitable [106].…”

“…Acquisition of JAK2 V617F, in particular, seems to genetically "fix" the already hyperactive JAK2-signaling present in age-associated stressed hematopoiesis [106]. It is also possible that MPN develops as a result of an inflammatory response to the JAK2 V617F clone that occurs frequently in elderly individuals [107].…”

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

“…The landmark discovery of the JAK2V617F mutation ushered a new era in the biology of MPN and established for the first time a link between an acquired genetic hit affecting the neoplastic clone and the major pathway involved in cytokine signaling, i.e., Janus Kinase (JAK)/Signal transducer and activator of transcription (STAT) [15].…”