Figure 2.

Main non-canonical signaling pathways activated by JAK2^V617F in Ph-negative MPNs. In PV patients, JAK2^V617F (depicted in red) activates the adhesion receptor Lu/BCAM through the RAP1-AKT signaling pathway, making their erythrocytes more adhesive. JAK2^V617F has also been described to promote aberrant signaling in the nucleus, where it prevents the binding of heterochromatin protein 1 alpha (HP1α) and inhibits the methylation of histones via protein arginine methyltransferase 5 (PRMT5) impairment. MPN patients with JAK2^V617F also seem to be insensitive to the anti-inflammatory cytokine IL-10, increasing TNF-α production through Toll-Like Receptor (TLR) signaling.