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

Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo and University of Pavia, Pavia, Italy.
Blood (Impact Factor: 9.78). 03/2008; 111(3):1686-9. DOI: 10.1182/blood-2007-07-101576
Source: PubMed

ABSTRACT We searched for JAK2 exon 12 mutations in patients with JAK2 (V617F)-negative myeloproliferative disorders. Seventeen patients with polycythemia vera (PV), including 15 sporadic cases and 2 familial cases, carried deletions or duplications of exon 12 in circulating granulocytes but not in T lymphocytes. Two of the 8 mutations detected were novel, and the most frequent ones were N542-E543del and E543-D544del. Most patients with PV carrying an exon 12 mutation had isolated erythrocytosis at clinical onset, unlike patients with JAK2 (V617F)-positive PV, most of whom had also elevations in white blood cell and/or platelet counts. Both patients with familial PV carrying an exon 12 mutation had an affected sibling with JAK2 (V617F)-positive PV. Thus, several somatic mutations of JAK2 exon 12 can be found in a myeloproliferative disorder that is mainly characterized by erythrocytosis. Moreover, a genetic predisposition to acquisition of different JAK2 mutations is inherited in families with myeloproliferative disorders.


Available from: Daniela Pietra, May 28, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of the JAK2 mutation in Philadelphia-chromosome negative myeloproliferative neoplasm (MPNs) in 2005 has heralded an era of rapid genetic discovery in the MPNs. This has lead to substantive gains in the understanding of the pathobiology of these diseases. Importantly, this has also lead to new treatment in the form of JAK inhibitors, as well as to clinical trials targeting other components thought to contribute to disease biology. However, given the number of new genomic alterations uncovered in the last several years, the relative contributions of each mutation to the development of a disease phenotype remains an area of robust investigation. Furthermore, the number of known mutations presents challenges to the practicing clinician in terms of what mutations to test for and the clinical significance of such mutations.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 06/2014; 27(2). DOI:10.1016/j.beha.2014.07.001 · 2.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The myeloproliferative disorders (MPDs) are a group of hematologic diseases with significant overlap in both clinical phenotype and genetic etiology. While most often caused by acquired somatic mutations in hematopoietic stem cells, the presence of familial clustering in MPD cases suggests that inheritance is an important factor in the etiology of this disease. Though far less common than sporadic disease, inherited MPDs can be clinically indistinguishable from sporadic disease. Recently, germline mutations in Janus kinase 2 (JAK2) and MPL, two genes frequently mutated in sporadic MPD, have been shown to cause inherited thrombocytosis. Study of the function of these mutant proteins has led to a new understanding of the biological mechanisms that produce myeloproliferative disease. In this review, we summarize the data regarding inherited mutations that cause or predispose to MPDs, with a focus on the biological effects of mutant proteins. We propose that defining inherited MPDs in this manner has the potential to simplify diagnosis in a group of disorders that can be difficult to differentiate clinically.
    Current Hematologic Malignancy Reports 09/2014; 9(4). DOI:10.1007/s11899-014-0232-3 · 2.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Calreticulin, an endoplasmic reticulum protein with multiple functions involving chaperone activity and calcium homeostasis, plays an important role in cellular proliferation and differentiation. Calreticulin dysfunction is known to be associated with different cancers. Very recently, calreticulin mutations have been identified in myeloproliferative neoplasms (MPNs), with a particularly high frequency in MPNs without Janus kinase 2 (JAK2) mutations, which exhibit clinical characteristics different from those with mutant JAK2. Here, we focus on the structure, function, and carcinogenicity of calreticulin, as well as its relationship with MPNs not involving JAK2 mutations.
    Leukemia and Lymphoma 08/2014; DOI:10.3109/10428194.2014.953153 · 2.61 Impact Factor