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JAK2^V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis

¹ Institute of Pathology, University Hospital, Freiburg, Germany
² Experimental Hematology, Department of Research, University Hospital, Basel, Switzerland
³ Department of Medical Biometry and Statistics and
⁴ Department of Biology I, University of Freiburg, Freiburg, Germany
⁵ Institute of Pathology, Heinrich Heine University, Duesseldorf, Germany and
⁶ Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine, University of Duesseldorf, Germany

Correspondence: Annette Schmitt-Graeff, Institute of Pathology, University Hospital, D-79108 Freiburg, Germany. E-mail: annette.schmitt-graeff{at}gmx.de

Background: Refractory anemia with ringed sideroblasts and marked thrombocytosis (RARS-T) was recently shown to be a JAK2-V617F mutation-related disorder. To determine the frequency and the prognostic significance of this mutation, we retrospectively evaluated 23 patients with platelet counts more than 600 x 10⁹/L, 15% ringed sideroblasts or more, and at least erythroid marrow dysplasia.

Design and Methods: An allele-specific polymerase chain reaction for JAK2-V617F was used to determine the allelic ratio of the mutated JAK2 allele in DNA samples extracted from bone marrow biopsies. Hematologic and survival data of the JAK2-V617F positive vs. the JAK2-V617F negative patients were statistically analyzed. Allele-specific polymerase chain reaction was also used to screen for MPL-W515 mutations.

Results: The JAK2-V617F mutation was present in 11 patients (48%) and was associated with significantly higher erythrocyte and white blood cell counts (p=0.009 and 0.011, respectively). In 6/11 RARS-T patients the allelic ratio of JAK2-V617F was above 50%, indicating the presence of cells homozygous for the mutation. In two of these patients a transition from JAK2-V617F heterozygosity to homozygosity was documented and was accompanied by rising platelet counts in sequential samples. The MPL-W515L mutation was detected in one JAK2-V617F negative patient. The relative risk of death was found to be lower in the mutation-positive group than in the mutation-negative group.

Conclusions: RARS-T patients with JAK2-V617F have a more favorable prognosis than those without the JAK2 mutation. The prevalence of homozygous JAK2-V617F mutation in RARS-T suggests that this entity is biologically distinct from essential thrombocythemia.

Key words: RARS-T, myelodysplastic syndrome, bone marrow biopsy, JAK2 genotyping, prognosis.

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