Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

The thickness of subduction plate boundary faults from the seafloor into the seismogenic zone

The thickness of an active plate boundary fault is an important parameter for understanding the strength and spatial heterogeneity of fault behavior. We have compiled direct measurements of the thickness of subduction thrust faults from active and ancient examples observed by ocean drilling and fi eld studies in accretionary wedges. We describe a general geometric model for subduction thrust décollements, which includes multiple simultaneously active, anastomosing fault strands tens of meters thick. The total thickness encompassing all simultaneously active strands increases to ~100–350 m at ~1–2 km below seafl oor, and this thickness is maintained down to a depth of ~15 km. Thin sharp faults representing earthquake slip surfaces or other discrete slip events are found within and along the edges of the tens-ofmeters- thick fault strands. Although fl attening, primary inherited chaotic fabrics, and fault migration through subducting sediments or the frontal prism may build mélange sections that are much thicker (to several kilometers), this thickness does not describe the active fault at any depth. These observations suggest that models should treat the subduction thrust plate boundary fault as <1–20 cm thick during earthquakes, with a concentration of postseismic and interseismic creep in single to several strands 5–35 m thick, with lesser distributed interseismic deformation in stratally disrupted rocks surrounding the fault strands

CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients

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Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea

Prior studies have reported high response rates with recombinant interferon-a (rIFN-a) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-a,we investigated the outcomes of pegylated-rIFN-a2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PVwho were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 monthswere 69.2%(43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P 5 .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was 26% (range, 284%to 47%) in patients achieving a CR vs 14%(range, 218% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU

Clinical significance of genetic aberrations in secondary acute myeloid leukemia

The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&amp;MPNr-EuroNet (COST action BM0902) study

Item does not contain fulltextReliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant

Seismic evidence for fluids in fault zones on top of the subducting Cocos Plate beneath Costa Rica

Author Posting. © The Authors, 2010. This article is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 181 (2010): 997-1016, doi:10.1111/j.1365-246X.2010.04552.x.In the 2005 TICOCAVA explosion seismology study in Costa Rica we observed crustal turning waves with a dominant frequency of ~10 Hz on a linear array of short-period seismometers from the Pacific Ocean to the Caribbean Sea. On one of the shot records, from Shot 21 in the backarc of the Cordillera Central, we also observed two seismic phases with an unusually high dominant frequency (~20 Hz). These two phases were recorded in the forearc region of central Costa Rica and arrived ~7 s apart and 30 to 40 s after the detonation of Shot 21. We considered the possibility that these secondary arrivals were produced by a local earthquake that may have happened during the active-source seismic experiment. Such high-frequency phases following Shot 21 were not recorded after Shots 22, 23, and 24, all in the backarc of Costa Rica, which might suggest that they were produced by some other source. However, earthquake dislocation models cannot produce seismic waves of such high frequency with significant amplitude. In addition, we would have expected to see more arrivals from such an earthquake on other seismic stations in central Costa Rica. We therefore investigate whether the high-frequency arrivals may be the result of a deep seismic reflection from the subducting Cocos plate. The timing of these phases is consistent with a shear wave from Shot 21 that was reflected as a compressional (SxP) and a shear (SxS) wave at the top of the subducting Cocos slab between 35 and 55 km depth. The shift in dominant frequency from ~10 Hz in the downgoing seismic wave to ~20 Hz in the reflected waves requires a particular seismic structure at the interface between the subducting slab and the forearc mantle in order to produce a substantial increase in reflection coefficients with frequency. The spectral amplitude characteristics of the SxP and SxS phases from Shot 21 are consistent with a very high Vp/Vs ratio of 6 in ~5 m thick, slab-parallel layers. This result suggests that a system of thin shear zones near the plate interface beneath the forearc is occupied by hydrous fluids under near-lithostatic conditions. The overpressured shear zone probably takes up fluids from the downgoing slab, and it may control the lower limit of the seismogenic zone.This work was funded by the US National Science Foundation MARGINS programme

Structure and lithology of the Japan Trench subduction plate boundary fault

The 2011 Mw9.0 Tohoku-oki earthquake ruptured to the trench with maximum coseismic slip located on the shallow portion of the plate boundary fault. To investigate the conditions and physical processes that promoted slip to the trench, Integrated Ocean Drilling Program Expedition 343/343T sailed 1 year after the earthquake and drilled into the plate boundary ∼7 km landward of the trench, in the region of maximum slip. Core analyses show that the plate boundary décollement is localized onto an interval of smectite-rich, pelagic clay. Subsidiary structures are present in both the upper and lower plates, which define a fault zone ∼5–15m thick. Fault rocks recovered from within the clay-rich interval contain a pervasive scaly fabric defined by anastomosing, polished, and lineated surfaces with two predominant orientations. The scaly fabric is crosscut in several places by discrete contacts across which the scaly fabric is truncated and rotated, or different rocks are juxtaposed. These contacts are inferred to be faults. The plate boundary décollement therefore contains structures resulting from both distributed and localized deformation. We infer that the formation of both of these types of structures is controlled by the frictional properties of the clay: the distributed scaly fabric formed at low strain rates associated with velocity-strengthening frictional behavior, and the localized faults formed at high strain rates characterized by velocity-weakening behavior. The presence of multiple discrete faults resulting from seismic slip within the décollement suggests that rupture to the trench may be characteristic of this margin

IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis

In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia (ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P<0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P=0.04), and less likely to display complex karyotype, in blast-phase disease (P<0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P<0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7–5.2), but not IDH mutational status (P=0.55; HR 1.3, 95% CI 0.5–3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P=0.04) and blast-phase MPN (P=0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes