Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders

Pietra, Daniela; Li, Sai; Brisci, Angela; Passamonti, Francesco; Rumi, Elisa; Theocharides, Alexandre; Ferrari, Maurizio; Gisslinger, Heinz; Královics, Róbert; Cremonesi, Laura; Skoda, Radek C.; Cazzola, Mario

doi:10.1182/blood-2007-07-101576

Cited by 272 publications

(243 citation statements)

References 24 publications

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“…47,48 • JAK2 exon 12 mutations are rare in ET or PMF, and their occurrence in PV is almost always associated with the absence of JAK2V617F and the presence of a subnormal serum erythropoietin level. 46,49 • The incidence of MPL mutations in MPN are too low (see above) to warrant their routine use in MPN diagnosis, except for clarification of equivocal morphology in the diagnosis of ET or PMF. 7 • JAK2 and MPL mutations do not occur in healthy subjects or in those with non-clonal causes of myeloproliferation.…”

Section: Jak2 and Mpl Mutation Screening In Routine Clinical Practicementioning

confidence: 99%

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

Tefferi

Noël

Hanson

2011

The Journal of Molecular Diagnostics

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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

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Section: Jak2 and Mpl Mutation Screening In Routine Clinical Practicementioning

confidence: 99%

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

Tefferi

Noël

Hanson

2011

The Journal of Molecular Diagnostics

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“…However, the V617F mutation renders the JAK2 protein constitutively active in the absence of a corresponding stimulus. Mutations in other parts of the gene, including exon 12, have also been observed in a sub group of MPN patients [8,9]. The identification of such a frequently mutated gene prompted further investiga tion into its role in the development of the disease.…”

Section: Mutations Affecting the Jak-stat Signaling Pathwaymentioning

confidence: 99%

Molecular basis and clonal evolution of myeloproliferative neoplasms

Cleary

Královics

2013

Clinical Chemistry and Laboratory Medicine (CCLM)

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Myeloproliferative neoplasms (MPNs) repre sent a group of diseases that affect the myeloid lineage, characterized by the presence of an excess of terminally differentiated myeloid cells. Defects causing clonal hematopoiesis are a key factor in the emergence of these diseases. Throughout the years, a number of causative defects have been identified, predominantly affecting cytokine signaling and gene expression regulation. This review aims to provide an update on the current status of the MPN field in relation to identification of molecular defects involved in the disease and its clonal evolution.

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“…The most frequently mutated amino-acid sequences span from 542 to 544. 17,112 In vitro studies demonstrated that JAK2 exon 12 mutations activate multiple pathways that are associated with erythropoietin signaling. More importantly, one mutation studied in detail resulted in the development of a myeloproliferative phenotype in a mouse model.…”

Section: Jak2 Mutationsmentioning

confidence: 99%

“…Patients with JAK2 exon 12 mutations typically present with a myeloproliferative syndrome accompanied by isolated erythrocytosis with suppressed erythropoietin production. 17,112 In addition, base-pair substitutions or deletions within the JH2 domain were identified not only in MPD but also in rare cases of acute leukemias and lymphoid disorders as summarized in Table 3.…”

Section: Jak2 Mutationsmentioning

confidence: 99%