Possible Selection for the Jak2 V617F Mutation in Bone Marrow Failure

The acquired JAK2 V617F mutation has been well documented to be common in the classical myeloproliferative disorders. As it is an activating mutation in a kinase involved in proliferative signaling in hematopoietic cells, it is presumed to play an etiopathogenic role. The same acquired JAK2 V617F mutation has been described in other hematological disorders such as myelodysplastic syndrome with a prevalence which, though much lower than in myeloproliferative disorders, exceeds what could be attributed to the chance coincidence of two rare disorders. The direction of causality in this association is unclear. CASE DESCRIPTION: A 42 year old woman initially presented at the age of six with anemia and was subsequently diagnosed with congenital dyserythropoietic anemia (CDA) type I. At initial presentation her other blood counts, including platelets, were normal. When she returned to hematology clinic as an adult, her anemia persisted, but she had elevated platelet and white blood counts. Bone marrow biopsy showed hypercellularity with increased representation of the myeloid and megakaryocyte lineages. It also showed megaloblastoid dyserythropoiesis and binucleate erythroid precursors. These changes are consistent with essential thrombocythemia superimposed on CDA type I. The marrow cells were heterozygous for the JAK2 V617F mutation.

DISCUSSION: This patient has a unique pairing of congenital dyserythropoietic anemia and a myeloproliferative disorder. No archival tissue is available so it is impossible to be certain she did not have the JAK2 V617F mutation on initial presentation, although the normal platelet and white blood count at age 6 support the inference that the myeloproliferative disorder arose later. Among patients with essential thrombocythemia, those who have the JAK2 V617F mutation tend to have higher hemoglobin levels, though in her case the development of the JAK2 V617F mutation did not lead to amelioration of her anemia. We hypothesize that the hematopoietic failure state associated with CDA may, like that of myelodysplasia, create an environment in which a genetically-mediated proliferative advantage due to an acquired mutation may be especially favored, and may thus have been a factor in the development of the myeloproliferative disorder.