1951, William Dameshek (1900−1969) penned an editorial in Blood highlighting shared phenotype (i.e., trilineage proliferation, splenomegaly, bone marrow fibrosis) among the myeloproliferative and related myeloid neoplasms, including chronic myeloid leukemia (CML; then referred to as “chronic granulocytic leukemia”), polycythemia vera (PV), essential thrombocythemia (ET; then referred to as “megakaryocytic leukemia”), and primary myelofibrosis (PMF; then referred to as “idiopathic or agnogenic myeloid metaplasia of spleen”).¹ He also discussed transitional (e.g., post-PV myelofibrosis) and pre-fibrotic states and contended that these “myeloproliferative disorders” were closely interrelated and represented variable manifestations of a constitutively-driven bone marrow proliferative activity arising from a “hitherto undiscovered stimulus”.¹

In 1960, Nowell and Hungerford described the Philadelphia chromosome that ultimately led to the identification of BCR::ABL1 as the disease-causing mutation in CML and the successful launching of imatinib (ABL tyrosine kinase inhibitor) as a disease-modifying drug therapy. By contrast, the molecular basis of PV, ET, and PMF remained elusive until the March, 2005 breakthrough communication by James et al., describing a novel Janus kinase 2 JAK/STAT activating mutation (JAK2V617F located in the auto-inhibitory JH2 pseudo-kinase domain — a G to T somatic mutation at nucleotide 1849, in exon 14, resulting in the substitution of valine to phenylalanine at codon 617) in PV, ET and PMF (discovery patent filing in October 2004).² The authors utilized short interfering RNA to knock down JAK2 expression and demonstrated the essential role of JAK2 in erythropoietin-independent growth in PV (Figure 1).