Therapy with JAK2 inhibitors for myeloproliferative neoplasms

Abstract

The development of JAK2 inhibitors followed the discovery of activating mutation of JAK2 (JAK2V617F) in patients with classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN). It is now known that mutations activating the JAK-STAT pathway are ubiquitous in Ph-negative MPN, and that the deregulated JAK-STAT pathway plays a central role in the pathogenesis of these disorders. JAK2 inhibitors thus are effective in patients both with and without the JAK2V617F mutation. This article reviews the rationale for using JAK2 inhibitors in Ph-negative MPN, and the results of more recent clinical trials with these drugs.

Figure 1

Structure of JAK kinases and domains

Figure 2. Central role of JAK kinases in Pathogenesis of Ph-negative MPNs

JAK-STAT signaling is activated in most, if not all, patients with the classic Ph-negative MPNs. This can be due to direct (JAK2 exon 12, JAK2V617F) or indirect (MPLW515L/K, LNK and CBL mutations) activation of the JAK2 kinase. The presence of pro-inflammatory cytokines such as IL-6 also contributes to STAT activation. Besides STATs, JAK2 kinases can also activate other oncogenic pathways such as the PI3K and MAPK pathways. Nuclear JAK2 leads to epigenetic deregulation by phosphorylating histone proteins and blocking binding of epigenetic regulators such as HP1α. The final consequence of activation of these pathways is expression of genes associated with cellular proliferation and resistance to apoptosis.