The JAK2 mutation.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders with overproduction of mature myeloid blood cells, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). In 2005, several groups identified a single gain-of-function point mutation JAK2V617F in the majority of MPN patients. The JAK2V617F mutation confers cytokine independent proliferation to hematopoietic progenitor cells by constitutively activating canonical and non-canonical downstream pathways. In this chapter, we focus on (1) the regulation of JAK2, (2) the molecular mechanisms used by JAK2V617F to induce MPNs, (3) the factors that are involved in the phenotypic diversity in MPNs, and (4) the effects of JAK2V617F on hematopoietic stem cells (HSCs). The discovery of the JAK2V617F mutation led to a comprehensive understanding of MPN; however, the question still remains about how one mutation can give rise to three distinct disease entities. Various mechanisms have been proposed, including JAK2V617F allele burden, differential STAT signaling, and host genetic modifiers. In vivo modeling of JAK2V617F has dramatically enhanced the understanding of the pathophysiology of the disease and provided the pre-clinical platform. Interestingly, most of these models do not show an increased hematopoietic stem cell self-renewal and function compared to wildtype controls, raising the question of whether JAK2V617F alone is sufficient to give a clonal advantage in MPN patients. In addition, the advent of modern sequencing technologies has led to a broader understanding of the mutational landscape and detailed JAK2V617F clonal architecture in MPN patients.