A historical series of discoveries and scientific breakthroughs led to the initial description of myelofibrosis (MF) in the literature.1 While the root cause of MF development is yet to be explained, research in recent decades has advanced the genetic and molecular understanding of the disorder.

Microscopic Visualization of Blood Cells

The first breakthrough in the history of MF discovery was the invention and improved design of the light microscope in the 1600s, which allowed for the visualization of red blood cells, white blood cells, and platelets.1 

In 1658, Jan Swammerdam, a Dutch microbiologist, visualized the red blood cells of a frog under a microscope. Independently, in 1660, another Dutch microbiologist, Antonie van Leeuwenhoek, provided the first accurate description of red blood cells, obtained by pricking his own thumb, which he viewed under a microscope.1,2 Joseph Lieutaud described white blood cells in 1749, and Alfred François Donné identified and described platelets in 1842.1

Application of Microscopy to Disease Identification

In October 1845, following these microscope-enabled hematologic discoveries, John Hughes Bennett, an English pathologist working at the Royal Infirmary in Edinburgh, Scotland, first identified and described chronic myelogenous leukemia (CML) in a case report.1,3

CML was initially included as a classical myeloproliferative neoplasm; however, the identification of a specific causative cytogenetic mutation resulted in CML being classified as its own separate entity.1

First Description of Myelofibrosis in the Literature

In 1879, Gustav Heuck, a German surgeon, detailed the cases of 2 young patients who both presented with massive splenomegaly (caused by extramedullary hematopoiesis), bone marrow fibrosis, osteosclerosis, and leukoerythroblastosis, all of which underscored the differences of this new disorder — primary MF — from CML.1,3

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Discovery of Other Classical Myeloproliferative Neoplasms

Following Heuck’s identification of primary MF in 1879, Louis Henri Vaquez, a French physician, first identified and described polycythemia vera (PV) in 1892 when he reported the case of a 40-year-old man with chronic vascular congestion and marked erythrocytosis.1,3 

In 1903, William Osler further detailed distinguishing features of PV from relative polycythemia and secondary polycythemia3 when he described 4 patients with chronic cyanosis with polycythemia and splenic enlargement.1,4

In 1934, two Australian pathologists, Emil Epstein and Alfred Goedel, described the last of the 3 classical myeloproliferative neoplasms, essential thrombocythemia (ET). They reported a patient who presented with extreme thrombocytosis (over 3 times the normal values found in the blood) and recurrent mucocutaneous bleeding. Excessive platelet production was associated with megakaryocytic hyperplasia.1,3

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Myelofibrosis Discoveries in the Late 1900s

In 1951, William Dameshek coined the phrase “myeloproliferative disorders.” He theorized that a trilineage myeloproliferation formed a biological basis that unified CML, primary MF, PV, and ET, as these disorders presented with similar clinical features.1,3

Between 1967 and 1981, Philip Fialkow, an American physician, identified polymorphisms in the X-linked glucose-6-phosphate dehydrogenase locus and completed a series of laboratory studies that confirmed that the 3 classic myeloproliferative disorders (MF, PV, and ET) and CML were all clonal hematopoietic stem cell disorders.1,3,5-8

Concurrently, in 1960, Peter Nowell and David Hungerford, two American scientists at the University of Pennsylvania School of Medicine, discovered the unusually small Philadelphia (Ph) chromosome, which was present (or positive) in the leukocytes of patients with CML.3,9 The discovery of this unique cytogenetic mutation led to the differentiation of CML from primary MF, PV, and ET, which were then classified as the classical Ph-negative myeloproliferative neoplasms.3,10

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Paradigm Shift to the Genetics of Myeloproliferative Neoplasms

In 2005, four independent laboratories identified the gain-of-function mutation, JAK2 V617F, that presents in virtually all patients with PV and around 50% of patients with MF and ET.11-14 This discovery led to a historical paradigm shift in defining and diagnosing myeloproliferative neoplasms. Instead of thinking about what was not present (Ph-negative disorders), researchers began to look for what was present on the molecular and genetic levels, leading to the subsequent discoveries of CALR-positive and MPL-positive cases of MF.15

Increasing knowledge about cytogenetic and molecular classifications of patients with MF allows for the identification of prognostic indicators for improved risk stratification and selection of the most effective and targeted therapies on a case-by-case basis.15

Read more about MF genetics


  1. Tremblay D, Yacoub A, Hoffman R. Overview of myeloproliferative neoplasms: history, pathogenesis, diagnostic criteria, and complications. Hematol Oncol Clin North Am. 2021;35(2):159-176. doi:10.1016/j.hoc.2020.12.001
  2. Antonie van Leeuwenhoek. Britannica. Accessed December 29, 2022.
  3. Tefferi A. Myeloproliferative neoplasms: a decade of discoveries and treatment advances. Am J Hematol. 2016;91(1):50-58. doi:10.1002/ajh.24221
  4. Osler W. Chronic cyanosis, with polycythaemia and enlarged spleen: a new clinical entityAm J Med Sci. 2008;335(6):411-417. doi:10.1097/MAJ.0b013e318175d13d 
  5. Jacobson RJ, Salo A, Fialkow PJ. Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis. Blood. 1978;51(2):189-194. doi:10.1182/blood.V51.2.189.189
  6. Fialkow PJ, Faguet GB, Jacobson RJ, Vaidya K, Murphy S. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood. 1981;58(5):916-919. doi:10.1182/blood.V58.5.916.916
  7. Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L. Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med. 1976;295(17):913-916. doi:10.1056/NEJM197610212951702
  8. Fialkow PJ, Gartler SM, Yoshida A. Clonal origin of chronic myelocytic leukemia in man. Proc Natl Acad Sci U S A. 1967;58(4):1468-1471. doi:10.1073/pnas.58.4.1468
  9. Koretzky GA. The legacy of the Philadelphia chromosome. J Clin Invest. 2007;117(8):2030-2032. doi:10.1172/JCI33032
  10. Odenike O. How I treat the blast phase of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood. 2018;132(22):2339-2350. doi:10.1182/blood-2018-03-785907
  11. Levine RL, Loriaux M, Huntly BJP, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood. 2005;106(10):3377-3379. doi:10.1182/blood-2005-05-1898
  12. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148. doi:10.1038/nature03546
  13. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-1790. doi:10.1056/NEJMoa051113
  14. Baxter EJ, Scott LM, Campbell PJ, et al; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054-1061. doi:10.1016/S0140-6736(05)71142-9
  15. Pemmaraju N, Moliterno AR. From Philadelphia-negative to JAK2-positive: effect of genetic discovery on risk stratification and management. Am Soc Clin Oncol Educ Book. 2015;35:139-145. doi:10.14694/EdBook_AM.2015.35.139

Reviewed by Kyle Habet, MD, on 12/31/2022.