Myeloproliferative disorders

Abstract

In 1951 William Dameshek classified polycythemia vera (PV), essential thombocytosis (ET), and primary myelofibrosis (PMF) as pathogenetically related myeloproliferative disorders (MPD). Subsequent studies demonstrated that PV, ET, and PMF are clonal disorders of multipotent hematopoietic progenitors. In 2005, a somatic activating mutation in the JAK2 nonreceptor tyrosine kinase (JAK2V617F) was identified in most patients with PV and in a significant proportion of patients with ET and PMF. Subsequent studies identified additional mutations in the JAK-STAT pathway in some patients with JAK2V617F(-) MPD, suggesting that constitutive activation of this signaling pathway is a unifying feature of these disorders. Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis. In addition, these observations provide a foundation for development of small molecule inhibitors of JAK2 that are currently being tested in clinical trials. This review will discuss our understanding of the pathogenesis of PV, ET, and PMF, the potential role of JAK2-targeted therapy, and the important unanswered questions that need to be addressed to improve clinical outcome.

Figure 1

Philadelphia chromosome negative myeloproliferative disorders: classification based on William Dameshek. Illustration by Debra Tyler.

Figure 2

Janus homology domains of the JAK family of kinases. The V617F mutation is within the JH2, or pseudokinase domain, whereas the exon 12 mutations in JAK2 are proximal to the JH2 domain. Illustration by Debra Tyler.

Figure 3

Model of leukemic transformation in MPD. Some patients develop JAK2V617F⁺ AML after JAK2V617F⁺ MPD, consistent with a JAK2V617F⁺ progenitor that undergoes leukemic transformation. However, some patients with JAK2V617F⁺ MPD transform to a JAK2V617F⁻ AML, consistent with a “pre-JAK2” clone, which is susceptible to leukemic transformation. Illustration by Debra Tyler.

Figure 4

Proposed model of MPD pathogenesis (adapted from ASH Education Program 2006). Illustration by Debra Tyler.