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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: 10.43). 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.

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Available from: Daniela Pietra, Aug 19, 2015
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    • "A subset of patients with JAK2V617F-negative PV or erythrocytosis were found to have somatic mutations in exon 12 of the JAK2 gene [Scott et al. 2007]. A number of different mutations within this exon have been discovered to date [Pietra et al. 2008]. These patients predominately have erythroid expansion without any associated thrombocytosis or leukocytosis and to date these mutations have not been identified in ET or PMF. "
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    ABSTRACT: The discovery of somatic mutations in the JAK-STAT signaling pathway was a major breakthrough in our understanding of the molecular pathogenesis of the myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocytosis, and primary myelofibrosis. This finding led to the development of small molecule inhibitors targeting Janus kinase (JAK) 2 and other JAK family members. Currently, there are a number of research and clinical trials ongoing with JAK inhibitors. While the appeal of inhibiting JAK2 is clear, studies to date suggest that JAK2 inhibitor monotherapy might not be sufficient to cause reductions in disease allele burden in MPN patients. There is compelling evidence that JAK inhibitors are improving symptoms and therefore quality of life for patients. It will be important to investigate the efficacy of JAK inhibitors in preclinical and clinical studies to better understand their effects, while at the same time pursuing alternative therapies which might offer benefit to MPN patients alone and in combination with JAK inhibitors.
    08/2011; 2(4):203-11. DOI:10.1177/2040620711410095
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    • "In addition, in murine retroviral transplant models, one of the mutant alleles (K539L) causes erythrocytosis . In contrast to the JAK2 V617F mutation, exon 12 mutations are restricted to PV [Pietra et al. 2008; Wang et al. 2008; Pardanani et al. 2007; Scott et al. 2007]. These findings suggest that the specific type of mutation in JAK2 may confer disparate clinical phenotypes , perhaps mediating differential effects on downstream signaling. "
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    ABSTRACT: Aberrant JAK-STAT signaling is a hallmark of myeloproliferative neoplasms (MPNs). These hyperproliferative disorders are classically associated with activating mutations in tyrosine kinases such as JAK2 and the thrombopoietin (TPO) receptor MPL. Activation of JAK-STAT signaling and responses to JAK2 inhibitors have been observed in MPN patients lacking JAK2 or MPL mutations, suggesting that other regulatory elements in the JAK-STAT pathway are altered. However, the molecular basis for this observation has been unclear. Recently, the role of inhibitory regulators of JAK-STAT signaling in MPN pathogenesis has been increasingly recognized. LNK is an adaptor protein that forms a negative feedback loop by binding to MPL and JAK2 and inhibiting downstream STAT activation. Murine models indicate that loss of LNK function can promote the development of a MPN phenotype. Several recent studies have identified novel LNK mutations in MPNs, thus validating this notion in humans. These findings represent a novel genetic paradigm of loss of negative feedback regulation of JAK-STAT activation in MPNs and have implications for the future development of targeted therapies in MPNs.
    02/2011; 2(1):11-9. DOI:10.1177/2040620710393391
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    • "Iron deficiency is common in those patients whose presentation overlaps with ET and should be investigated to exclude a second pathology. The JAK2 V617F mutation is present in more than 97% of PV patients and a further 1–2% will have an exon 12 mutation of JAK2 (Scott et al, 2007),(Pietra et al, 2008). Exon 12 mutations have not been documented in the context of ET or PMF. "
    British Journal of Haematology 03/2010; 149(3):352-75. DOI:10.1111/j.1365-2141.2010.08122.x · 4.96 Impact Factor
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