Myelofibrosis with myeloid metaplasia (MMM) is a clonal myeloproliferative disorder, characterized by splenomegaly and myelofibrosis. Like all myeloproliferative disorders, it is due to an acquired somatic mutation of a hematopoietic progenitor resulting in clonal erythrocytes, platelets, and granulocytes. A single acquired point mutation of JAK2 1849G>T (V617F), a tyrosine kinase with a key role in signal transduction from growth factor receptors, occurs in 50%–97% of patients with MMM, essential thrombocythemia (ET) and polycythemia vera (PV). We studied 25 myelofibrosis patients with myeloid metaplasia and myelofibrosis complicating PV or ET. These were compared to 19 patients with secondary myelofibrosis of equivalent severity associated with pulmonary hypertension (PH) treated by epoprostenol. In these two groups we compared peripheral blood CD34 counts, clonality of granulocytes and platelets in peripheral blood, mutational status of JAK 2 kinase gene, and morphology of peripheral blood and bone marrow. Heterozygosity for JAK 2 1849G>T somatic mutation was seen in 17 of 23 (74%) patients with MMM including 10 of 15 patients (67%) with idiopathic myelofibrosis and 7 of 8 patients (88%) with myelofibrosis complicating PV or ET, but was absent in all 19 patients with myelofibrosis associated with PH (P<0.0001, Fisher exact test 2 tailed). The number of peripheral blood CD 34 cells was significantly higher in patients with MMM compared to patients with secondary myelofibrosis associated with PH; 1.1% (95% CI, 0.58%–1.64%) in patients with MMM versus 0.08% (95% CI, 0.04%–0.12%) in patients with PH, or 0.05% (95% CI, 0.03%–0.06%) in normal healthy controls (P<0.01). Further, patients with PH lacked dacrocytes, erythroid precursors, or myeloid precursors (leukoerythroblastic picture) on examination of the blood smear. Clonal hematopoiesis was found only in those women with marrow fibrosis due to MMM, PV and ET and not in patients with secondary marrow fibrosis (P < 0.0001).

We conclude that a high circulating CD34 count, clonal platelets and granulocytes, presence of dacrocytes, and JAK2 1849G>T (V617F) mutation of clonal progenitors are the intrinsic features present in patients with myelofibrosis due to myeloproliferative disorders and that these features are not due to the abnormal marrow architecture that is seen in secondary myelofibrosis.

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