Abnormal Megakaryopoiesis in Patients With A JAK2 Exon 12 Mutation May Be A Non-Cell-Autonomous Phenomenon

Linda M Scott

doi:10.4172/2329-8820.1000116

Abstract

Background: In contrast to patients with JAK2V617F-positive polycythemia vera, those patients with a JAK2 exon 12 mutation present with platelet counts within the normal range. Furthermore, the bone marrow samples from most JAK2 exon 12 mutation-positive patients lack the prominent clusters of large, bizarre-looking megakaryocytes that characterize classic JAK2V617F-positive polycythemia vera. This study examines the effects on megakaryopoiesis associated with the presence of a JAK2 exon 12 mutation. Results: These mutations were found to be present within the platelet population of affected individuals at levels comparable to those in paired granulocyte samples, suggesting that they do not profoundly affect the viability of platelets or their precursors. Furthermore, in vitro assays demonstrate that JAK2K539L is capable of interacting with and mediating intracellular signalling through the thrombopoietin receptor. An interesting phenomenon was identified when the genotype of individual atypical megakaryocytes present in the bone marrow was determined: only a proportion of those that may be observed in JAK2 exon 12 mutation-positive patients were positive for this mutation. Conclusions: It remains unclear why patients positive for a JAK2 exon 12 mutation do not have the elevated platelet counts typically observed in patients with classic JAK2V617F-positive PV. The analysis of megakaryocytes with atypical nuclear structure suggests that other hematopoietic or non-hematopoietic cells within the bone marrow environment of MPN patients may influence the phenotype of cells that themselves lack a JAK2 mutation.

Highlights

Polycythemia vera (PV), one of the myeloproliferative neoplasms (MPNs), is characterized by the predominant expansion of morphologically normal erythroid cells
Whereas patients with JAK2V617Fpositive PV characteristically have tri-lineage involvement, Janus kinase 2 (JAK2) exon 12 mutation-positive patients tend to present with an isolated erythrocytosis [13,14]; most individuals have normal leukocyte and platelet counts, approximately a fifth have elevated counts of either lineage
Two JAK2 exon 12 mutationpositive PV patients, for whom cell counts over a long period of time were available, were identified: Patient A had been treated for a decade, and Patient B for just over eight years (Figure 1)

Summary

Introduction

Polycythemia vera (PV), one of the myeloproliferative neoplasms (MPNs), is characterized by the predominant expansion of morphologically normal erythroid cells. Bone marrow samples from JAK2 exon 12 mutationpositive patients typically lack the prominent clusters of large, bizarrelooking megakaryocytes that characterize JAK2V617F-positive PV, small clusters of two to four megakaryocytes, some of which may appear atypical, can be identified [15,16]. The effects on megakaryopoiesis associated with the presence of a JAK2 exon 12 mutation have not been examined. In vitro assays as well as patient samples and haematologic data were used to determine the effects of a JAK2 exon 12 mutation on the viability and proliferation of megakaryocytic cells. In contrast to patients with JAK2V617F-positive polycythemia vera, those patients with a JAK2 exon 12 mutation present with platelet counts within the normal range. The bone marrow samples from most JAK2 exon 12 mutation-positive patients lack the prominent clusters of large, bizarre-looking megakaryocytes that characterize classic JAK2V617F-positive polycythemia vera. This study examines the effects on megakaryopoiesis associated with the presence of a JAK2 exon 12 mutation

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Results

Discussion

Conclusion