Myeloproliferative neoplasm historical perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Shyam Patel [3]

The first description of myeloproliferative neoplasm dates back to the late 19th century, when Sir Louis Vasquez studied a patient with excess red blood cells. Myeloproliferative neoplasm was first brought to attention as an important clinical entity by Dr. William Dameshek, an American hematologist, in 1951. In 2005, the link between the JAK2 mutation and polycythemia vera was discovered. The World Health Organization created diagnostic criteria for myeloproliferative neoplasms in 2008, and this was revised in 2016.

• In 1892, Sir Louis Vasquez described the first form of myeloproliferative disease in a patient. He described a patient with excess red blood cell production (eventually found to be polycythemia vera, liver enlargement (hepatomegaly), and spleen enlargement (splenomegaly). It was thought that excess hematopoietic cell production resulted in organ enlargement. This was later termed extramedullary hematopoiesis.^[1]

• In 1903, Sir William Osler later described a group of patients with elevated red blood cell counts.^[2]

• In 1934, Alfred Goedel and Emil Epstein found that patients with thrombocytosis without erythrocytosis was a separate disease entity (later coined as essential thrombocythemia).^[1]

• In 1940, Sir William Dameshek and Henthell described the clinical features of the myeloproliferative neoplasm now known as polycythemia vera. Patients were noted to have facial plethora, splenomegaly, elevated hemoglobin, and elevated platelet count.

• In 1951, Sir William Dameshek, an American hematologist, discovered myeloproliferative neoplasms. Dr. Dameshek was a pioneer in the field and paved the way for future investigations into the details of this condition. He grouped a variety of conditions together and classified these individual conditions are myeloproliferative neoplasms.^[3]

• In 1967, Fialkow and colleagues showed evidence for clonally-derived myelopoiesis, based on studies showing the presence of the same G6PD polymorphism in erythrocytes and granulocytes. These studies suggested that one clone gave rise to multiple cell types.^[1]

• In 1976, Adamson and colleagues showed evidence for panmyeloid clonal expansion, meaning that a single clone could give rise to multiple lineages including erythrocytes, granulocytes, and megakaryocytes.^[1]

• In 2005, Ross Levine and colleagues found that the JAK2 V617F mutation was the molecular basis for polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.^[4] High-throughput sequencing of DNA was performed in patients who were diagnosed with these myeloproliferative neoplasms. Healthy persons were found to not harbor this mutation, suggesting high specificity of the mutation for myeloproliferative neoplasm. It was noted that the JAK2 mutation resulted in a constitutively active tyrosine kinase.^{[5][6][7][8][9]} It was eventually noted that more than 95% of patients with polycythemia vera harbored the JAK2 V617F mutation, and 55-60% of patients with myelofibrosis had the mutation. The mutation was also found to be in 50% of patients with primary myelofibrosis.

• In 2006, Pikman and colleagues found that the MPL W515L mutation was associated with myeloproliferative neoplasms.^[10] It was noted that, in patients without the JAK2 V617F mutation, the MPL mutation served as the pathogenic stimulus for myeloproliferation via activation of JAK-STAT signaling.^[10]

• In 2007, Scott and colleagues discovered that JAK2 exon 12 mutations (which are distinct from the V617F mutation in exon 14) could result in polycythemia vera.^[11]

• In 2008, the World Health Organization developed original criteria for the diagnosis of myeloproliferative neoplasm.^[2]

• In 2009, Langemeijer and colleagues noted that TET2 and ASXL1 mutations and somatic copy-number loss were found to be associated with myeloproliferative neoplasms. These mutations were first found to be associated with myelodysplastic syndrome. These studies were conducted via single nucleotide polymorphism arrays and comparative genomic hybridization.

• In 2016, the World Health Organization developed a revision for the diagnostic criteria for myeloproliferative neoplasm.