Balkan Journal of Medical Genetics

EVALUATION OF THE JAK2V617F MUTATIONAL BURDEN IN PATIENTS WITH PHILADELPHIA CHROMOSOME NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: A SINGLE-CENTER EXPERIENCE
Popova-Labachevska M1, Panovska-Stavridis I1,*, Eftimov A2, Kapedanovska Nestorovska A2, Cevreska L1, Ivanovski M1, Ridova N1, Trajkova S1, Dimovski AJ2,*
*Corresponding Author: Associate Professor Irina Panovska-Stavridis, M.D., Ph.D., University Clinic of Hematology, UKIM-Faculty of Medicine, University Cyril and Methodious,” Majka Tereza 47, Skopje, RN Macedonia. Tel/Fax: +38923111749. E-mail: ukhematologija@t.mk and/or Professor Aleksandar J. Dimovski, M.D., Ph.D., Center for Biomolecular Pharmaceutical Analyses, UKIM-Faculty of Pharmacy, University “Ss Cyril and Methodius,” Majka Tereza 47, Skopje, RN Macedonia. Tel/Fax: +38923119694. E-mail: adimovski@ff.ukim.edu.mk
page: 31

INTRODUCTION

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical Philadelphia- negative (Ph-negative) myeloproliferative neoplasms (MPNs) characterized by a clonal expansion of the abnormal hematopoietic stem/progenitor cell [1]. Their natural history is marked by thrombohemorrhagic episodes and a potential for transformation in myelofibrosis (PV and ET) or acute leukemia (PMF and PV). The major goal of therapy is prevention and/or treatment of these complications [2]. For many years, there were no specific histological, cytogenetic, or molecular markers for these MPNs. The discovery of the unique gain-of-function somatic JAK2V617F mutation in patients with myeloproliferative disorders changed the diagnostic landscape of MPNs [3,4]. The mutation was found with a frequency of >95.0% in PV patients and 55.0-60.0% in ET and PMF patients, and it was soon adopted as a molecular criterion for these patients. It also helped delineate the molecular pathogenesis as well as the biological features of positive MPN patients [4]. Nevertheless, the “inquiry” how one single JAK2 V617F mutation incites expression of at least three different clinical phenotypes, i.e., PV, ET and PMF, is still open [5]. In the past few years, different hypotheses were proposed. One of them, named “the gene dosage hypothesis,” postulates a counterpart between clinical manifestations and the proportion of JAK2 (V617F) mutant alleles introducing the concept of allele burden or “mutational load theory” (ratio between a mutant and wild type JAK2 in hematopoietic cells) [5-7]. The studies that followed supported this hypothesis and showed that the JAK2V617F mutational load was associated with specific hematological, clinical parameters and different risks for thromboembolic complications [6]. Those results indicate that allele burden testing could be incorporated in the initial diagnostic work-up as additional parameters for patient risk stratification [7]. In order to further clarify these observations, we evaluated the level of the JAK2 mutant allele and its clinical implications in 134 JAK2V617F+ patients with different MPNs from the RN Macedonia.

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