as template, DHPLC allows the analysis of amplicons including more than one exon at time. For this reason, DHPLC assay is a good approach suitable to identify genetic aberrations occurring outside the specific mutational hot spot. Only the samples showing an abnormal chromatogram are subsequently sequenced. As an alternative, immunohistochemistry that detects, through cytoplasmic dislocation on NPM, 'all types' of NPM1 mutations, 3,4 could serve as first step for directing further molecular studies, i.e. restricting analysis for NPM1 exons other than exon-12 to AML cases that may turn out to be NPM cytoplasmicpositive in the absence of exon-12 NPM1 mutations. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia.
Acknowledgements
SummaryRecently several different JAK2 exon12 mutations have been identified in V617F negative polycythaemia vera (PV) or idiopathic erythrocytosis (IE) patients. The patients present with erythrocytosis, ligand-independent cell growth and low serum erythropoietin (EPO) levels. Within this group, a deletion of amino acids 542-543 (N542-E543del) of JAK2 is most prevalent. We have previously shown that in the presence of JAK2 V617F , suppressor of cytokine signalling 3 (SOCS3) is unable to negatively regulate EPO signalling and proliferation of V617F-expressing cells. Here we report a PV patient heterozygous for the somatic JAK2 N542-E543del mutation and a previously unreported germline mutation within the SH2 domain of SOCS3 (F136L). Interestingly, the SOCS3 F136L mutation was detected in a Japanese myeloproliferative disorder patient cohort at double the frequency of healthy controls. Cells expressing SOCS3 F136L had markedly elevated EPO-induced proliferation and extended EPO-induced JAK2 phosphorylation. Additionally, compared to wild-type SOCS3, mutant SOCS3 had an extended half-life in the presence of JAK2 and JAK2 N542-E543del . Our findings suggest that this lossof-function SOCS3 mutation may have contributed to disease onset by causing deregulated JAK2 signalling in the presence of a constitutively active JAK2 N542-E543del mutant.
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