Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

Abstract

JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. Morphology is the cornerstone of current diagnosis and classification in myeloid malignancies. 1 Cytochemical, immunophenotypic, cytogenetic, and molecular data enhance diagnostic accuracy and form the basis for the World Health Organization classification of myeloid malignancies into five main categories 2 : acute myeloid leukemia, myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and platelet-derived growth factor receptor gene or fibroblast growth factor receptor 1 gene rearranged myeloid/lymphoid neoplasms associated with eosinophilia. The World Health Organization MPN category includes eight subcategories: chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and MPN unclassifiable. 1 Among these subcategories, the first four (ie, chronic myelogenous leukemia, PV, ET, and PMF) are currently referred to as "classic" MPNs, because they were included in the original description of myeloproliferative disorders by William Dameshek. 3 In general, current evidence supports consideration of all myeloid malignancies, including MPN, as clonal stem cell diseases.JAK2 and MPL mutations occur across the spectrum of myeloid malignancies, including MPN, MDS, MDS/MPN, and acute myeloid leukemia (Table 1). 4 -7 These mutations are most prevalent in the BCR-ABL1-negative classic MPN (ie, PV, ET, and PMF), which are morphologically characterized by the absence of both cellular dysplasia

Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations

“…A strategy for the efficient combination of JAK2 V617F, JAK2 exon 12 and MPL exon 10 mutations detection assays in suspected myeloproliferative neoplasms is discussed. These guidelines are broadly in line with the screening strategy proposed by Tefferi et al (). A step‐wise algorithm for supplementary JAK2 exon 12 or MPL exon 10 mutation analysis is both cost‐effective and an efficient use of available material and may reduce the need for a bone marrow biopsy in some patients.…”

Molecular Genetics of Myeloproliferative Disorders

“…This has been identified as MPLW515L. The frequency of MPLW515L is at 4% for ET and 11% for PMF, which has not been identified for PV (Vakil and Tefferi, 2011;Campregher et al, 2010;Tefferi et al, 2011).…”

“…SH2B adaptor protein 3 (LNK) (12q24,12) negatively regulates JAK 2 cytokine signalling which encodes for a membrane bound receptor protein that negatively regulates JAK2 signalling. Mutations are found in less than 10% of patients in the blast phase of the MPNs and usually not seen in the chronic phase (Campregher et al, 2010;Tefferi et al, 2011). Patients having LNK mutations presented with an increase STAT activation, suggesting that the loss of function caused by LNK is analogous to JAK2 and MPL gain of function mutations (Campregher et al, 2010;Lasho et al, 2010).…”

Considerations and Recommendations for a New Molecular Diagnostic Algorithm for the Myeloproliferative Neoplasms

“…Previous efforts to streamline this process, in which BCR-ABL1 testing was advocated as a firstor second-line investigation (Schnittger et al, 2012;Bench et al, 2013), require revisiting in light of the description of CALR mutations to avoid en masse screening deemed scientifically irrational and economically irresponsible in this clinical scenario (Tefferi et al, 2011).…”