Secondary Myelofibrosis in the Naturel History of JAK2, MPL and CALR Mutated Myeloproliferative Neoplasms

The WHO classification of the Myeloprolferative Neoplasms (MPN) distinguishes Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PMF). Myelofibrosis (MF) is not a disease because reticulin and collagen fibrosis are produced by polyclonal fibroblasts in response to cytokines released from the clonal granulocytic and megakaryocytic progenitor cells in myeloproliferative disorders (MPD) in patients with ET and PV. The Hannover and Cologne Bone Marrow classification defined chronic or primary megakaryocytic granulocytic myeloproliferation (PMGM) as the third distinct prefibrotic MPN without features of PV. Vainchenker (2005) discovered the JAK2V617F somatic mutation as the driver cause of ET, trilinear PV of erythrocytic, megakaryocytic and granulocytic myeloproliferation (EMGM) and myeloid neoplasia of the spleen with secondary MF. Prefibrotic JAK2V617F mutated ET comprises three phenotypes: normocellular ET, ET with PV features in blood and bone marrow (prodromal PV) and hypercellular ET with predominant megakaryocytic granulocytic myeloproliferation (EMGM or masked PV) and moderate splenomegaly. JAK2V617F mutated ET and PV are featured by medium sized to large (pleomorphic) megakaryocytes with only a few giant forms. JAK2 exon 12 mutated MPN usually present with idiopathic erythrocythemia or early PV. Bone marrow histology in MPL515 positive ET and MF show clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei in a normocellular bone marrow with no features of PV already described in 1988 (Thiele). Bone marrow histology in prefibrotic CALR mutated ET and MF is associated with PMGM and dominated by dense clusters of large immature megakaryocytes with hypolobulated bulky (cloude-like) hyperchromatic nuclei, which are never seen in JAK2V617F, JAK2 exon 12 and MPL515 mutated MPN. Disease burden in JAK2, MPL and CALR mutated MPN is best reflected by the degree of anemia, splenomegaly, mutation allele burden, bone marrow cellularity and myelofibrosis