Immunological Consequences of JAK Inhibition: Friend or Foe?

Over the last decade, unparalleled advances have been made within the field of 'Philadelphia chromosome'-negative myeloproliferative neoplasms (MPN) regarding both disease pathogenesis and therapeutic targeting. The discovery of deregulated JAK-STAT signalling in MPN led to the rapid development of JAK inhibitor agents, targeting both mutated and wild-type JAK, which have significantly altered the therapeutic paradigm for patients with MPN. Although the largest population treated with these agents incorporates those with myelofibrosis, increasing data supports potential usage in other MPNs such as essential thromocythaemia and polycythaemia vera. Many MPNs are associated with a hyperinflammatory state and deregulation of immune homeostasis. Over the last few years, research has focused on attempting to decipher the complex and context-dependent changes that contribute to this immune deregulation. Moreover, very recent studies have demonstrated significant JAK inhibitor-mediated effects within the T cell, natural killer cell and dendritic cell compartments following exposure to JAK inhibitors. In parallel, case reports of infections occurring following exposure to ruxolitinib, many of which are atypical, have focused research efforts on delineating JAK inhibitor-associated immunological consequences. Within this review article, we will describe what is currently known about MPN-associated immune deregulation and JAK inhibitor-mediated immunomodulation.

Targeting of the Hedgehog pathway in myeloid malignancies: still a worthy chase?

Deregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic intervention. Although initial haematological interest focused on the therapeutic targeting of this pathway in chronic myeloid leukaemia), small molecule inhibitors targeting the Hh pathway are now being tested in a range of other myeloid disorders, including myelofibrosis, myelodysplasia and acute myeloid leukaemia. In this review we will evaluate the rationale for targeting of the Hh pathway in myeloid diseases and discuss the novel agents that have entered the clinical arena. We will discuss pre-clinical models, emerging clinical trial data, and suggest how these targeted therapies may address current unmet medical needs. Finally, we will explore potential limitations of these therapies due to the emergence of secondary resistance mechanisms and speculate on future developments within this arena.