AML1/MDS1/EVI1 Induces Essential Thrombocythemia in Mice Independently of Jak2 Mutations.

The molecular etiology of subgroups of essential thrombocythemia (ET), as well as some other myeloproliferative disorders (MPDs) has been recently better understood by the identification of an activating somatic point mutation (Valine 617 to Phenylalanine) in Jak2 detected in patients with MPDs. Approximately 23%–57% of ET patients harbor this mutation, which is thought to be one of the dominant factors contributing to the disease. However, the pathways disrupted in at least half of ET patients who have wild type Jak2 are not known. The fusion gene AML1/MDS1/EVI1 (AME), a product of the t(3;21)(q26;q22) translocation, is associated with several hematopoietic disorders, primarily chronic myelogenous leukemia and acute myeloid leukemia, and to a lesser extent with ET. We have investigated the role of AME by generating C57BL/6J mice that express this fusion oncogene in their bone marrow after bone marrow infection and transplantation. After a latency of 12 ± 1.8 months, all the reconstituted mice invariably developed an ET-like disease. The disease was fatal and the animals died of anemia probably caused by bleeding. Until 1–2 weeks before death, at which time the mice were severely cytopenic, the peripheral blood hemoglobin and leukocyte counts of the reconstituted AME mice were normal. The only striking difference was the platelet counts, which were consistently above the normal range (1456–3153 and 940–1608 K/ml for AME and control mice, respectively, p=0.00029). Platelets appeared dysplastic with anisocytosis, various degrees of degranulation, and giant size. The bone core biopsies of AME mice were especially remarkable for large and giant megakaryocytes with a tendency for clustering. Touch preparations of the biopsies showed progressive maturation in the granulocytic and erythroid precursor cell lines, a normal myeloid to erythroid ratio and no evidence of dyshematopoiesis. These finding coupled with markedly increased levels of TPO but normal concentrations of c-Mpl and Epo-R are concordant with the morphologic and laboratory features of patients with ET. The sequence analysis of exon 12 of Jak2 demonstrated no guanine-to-thymine transversion at nucleotide 1849 in all AME mice tested. These data are valuable because they provide a novel mouse model for understanding the deregulated pathways in ET patients with wild-type Jak2.