The Role of Reactive Oxygen Species in Myelofibrosis and Related Neoplasms

Figure 1

Sustained NF-E2 expression likely elicits a pronounced oxidative stress milieu with excessive ROS giving rise to myeloid expansion with leukocytosis and excessive thrombocytosis and inflammation-mediated in vivo activation of leukocytes and platelets, thereby further promoting a sustained, self-perpetuating release of inflammatory products. In this vicious circle, an oxidative stress burden with NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic differentiation. Increasing oxidative stress-induced DNA damage of hematopoietic stem cells (HSCs) elicits genomic instability and clonal MPN evolution with accumulation of mutations ultimately terminating in myelofibrotic and leukemic transformation. A relative deficiency of Nrf2 may also result in expansion of the HSC and progenitor cell compartment and ultimately migration of HSCs from their stem cell niches into the circulation (“leaving the burning nest”) to seed in the spleen and liver (myelofibrosis with myeloid metaplasia). The vicious circle may be locked by early intervention with interferon-alpha2 (stopping the fuel to the fire) in combination with a JAK1-2 inhibitor (e.g., ruxolitinib) and a statin, the latter agents “cooling down the system” by their highly potent anti-inflammatory properties which may actually be enhanced (synergism) when being administered simultaneously. With permission from Leukemia Research [29].