CONSEQUENCES OF BRCA1 EPIGENETIC SILENCING ON HOMOLOGOUS RECOMBINATION AND DISEASE PROGRESSION IN MYELOID NEOPLASMS

Myeloid malignancies are hematological disorders encompassing chronic myeloid neoplasms to acute leukemias. In recent years, insight from genome-wide discovery studies has improved our understanding and ability to predict prognosis and treatment outcome. Despite these advances, there remains considerable clinical heterogeneity within current classification systems as these diseases often present with diverse and overlapping pathological features. At the same time, there has been limited success in translating these findings into effective therapeutics to improve overall survival. Increasingly, it is recognized that these complex and dynamic molecular changes converge into a small number of biological pathways. Therefore, a pathway-driven approach identifying commonly perturbed processes could yield greater success in developing broadly applicable therapeutics. One promising candidate is the homologous recombination (HR) pathway responsible for repairing double-stranded breaks, since most myeloid neoplasms are characterized by gross chromosomal instability. To objectively assess HR repair in fresh mononuclear cells from myeloid malignancy patients, we developed an ex vivo, short-term assay that determines HR repair based on nuclear RAD51 foci induction after DNA damage. Using this technique, we observed HR defects in 9 of 21 myeloid malignancy samples. Since there is little evidence for mutational alterations in HR genes, we screened HR gene promoters and observed BRCA1 promoter methylation in a significant subpopulation (22/96 samples) that strongly associates with disrupted HR repair. To our knowledge, this is the first report linking BRCA1 methylation to HR defects in patient samples. Next, we validated the patient samples findings by silencing BRCA1 expression in AML cells that recapitulated the HR defects. We treated AML cells with poly(ADP-ribose) polymerase (PARP) inhibitors and observed increased sensitivity with BRCA1 repression, providing a mechanistic justification for previous studies highlighting toxicities with PARP inhibitors in myeloid malignancies. The high prevalence of BRCA1 silencing led us to consider additional roles in driving myeloid disease, as it is known to repress microRNA-155 (miR-155) that is frequently elevated in myeloid malignancies. By correlating gene expression in the patient samples, we found an inverse correlation between BRCA1 and miR-155 levels. miR-155 is frequently elevated in myeloid malignancies and its targets include key regulators of inflammation (SHIP1) and myeloid differentiation (PU.1). Our results here show that BRCA1 loss due to promoter methylation not only contributes to HR defects, but also contributes to disease progression via miR-155 upregulation

MESSENGER Observations of Fast Plasma Flows in Mercury’s Magnetotail

We present the first observation of fast plasma flows in Mercury’s magnetotail. Mercury experiences substorm activity phenomenologically similar to Earth’s; however, field‐of‐view limitations of the Fast Imaging Plasma Spectrometer (FIPS) prevent the instrument from detecting fast flows in the plasma sheet. Although FIPS measures incomplete plasma distributions, subsonic flows impart an asymmetry on the partial plasma distribution, even if the flow directions are outside the field of view. We combine FIPS observations from 387 intervals containing magnetic field dipolarizations to mitigate these instrument limitations. By taking advantage of variations in spacecraft pointing during these intervals, we construct composite plasma distributions from which mean flows are determined. We find that dipolarizations at Mercury are embedded within fast sunward flows with an averaged speed of ~300 km/s compared to a typical background flow of ~50 km/s.Plain Language SummarySimilar to Earth, Mercury has a global magnetic field that forms a protective cavity, known as the magnetosphere, within the solar wind. The solar wind compresses the dayside magnetosphere, while stretching the nightside magnetosphere behind the planet. Variations within the solar wind cause dynamic activity within Mercury’s magnetosphere, with a process known as magnetic reconnection mediating the interaction. Magnetic reconnection changes the topology of magnetic field lines and transfers energy and momentum from the magnetic field to the plasma within it. At Earth, magnetic reconnection in the nightside magnetosphere drives fast flows of plasma toward the planet, which when nearing the planet are slowed and diverted. These flows cannot be identified directly at Mercury because of limitations of the MESSENGER spacecraft measurements collected there. This research paper develops a new statistical technique to identify and characterize these fast flows at Mercury.Key PointsMultiple FIPS plasma observations from the MESSENGER spacecraft have been combined statistically to determine average flowsObservations collected during dipolarizations produce an average plasma flow of ~300 km/s compared to ~50 km/s during background intervalsSeveral dipolarizations are required to unload Mercury’s magnetotail during a substorm, and some flows may reach the planet’s surfacePeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146314/1/grl58028.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146314/2/grl58028_am.pd

Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression.</p> <p>Results</p> <p>Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness.</p> <p>Conclusions</p> <p>Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.</p

Large‐Amplitude Oscillatory Motion of Mercury’s Cross‐Tail Current Sheet

We surveyed 4 years of MESSENGER magnetic field data and analyzed intervals with observations of large‐amplitude oscillatory motions of Mercury’s cross‐tail current sheet, or flapping waves, characterized by a decrease in magnetic field intensity and multiple reversals of BX, oscillating with a period on the order of ~4 – 25 seconds. We performed minimum variance analysis (MVA) on each flapping wave event to determine the current sheet normal. Statistical results showed that the flapping motion of the current sheet caused it to warp and tilt in the y‐z plane, which suggests that these flapping waves are kink‐type waves propagating in the cross‐tail direction of Mercury’s magnetotail. The occurrence of flapping waves shows a strong preference in Mercury’s duskside plasma sheet. We compared our results with the magnetic double‐gradient instability model and examined possible flapping wave excitation mechanism theories from internal (e.g., finite gyroradius effects of planetary sodium ions Na+ on magnetosonic waves) and external (e.g., solar wind variations and K‐H waves) sources.Key PointsLarge‐amplitude oscillations of Mercury’s cross‐tail current sheet (or flapping waves) with period of ~4 – 25 s were observedFlapping motion of Mercury’s cross‐tail current sheet warped and tilted the current sheet in the y‐z planeFlapping waves preferentially occur in Mercury’s duskside current sheetPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156232/2/jgra55803.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156232/1/jgra55803_am.pd

Properties and Acceleration Mechanisms of Electrons Up To 200 keV Associated With a Flux Rope Pair and Reconnection X‐Lines Around It in Earth's Plasma Sheet

The properties and acceleration mechanisms of electrons (<200 keV) associated with a pair of tailward traveling flux ropes and accompanied reconnection X-lines in Earth's plasma sheet are investigated with MMS measurements. Energetic electrons are enhanced on both boundaries and core of the flux ropes. The power-law spectra of energetic electrons near the X-lines and in flux ropes are harder than those on flux rope boundaries. Theoretical calculations show that the highest energy of adiabatic electrons is a few keV around the X-lines, tens of keV immediately downstream of the X-lines, hundreds of keV on the flux rope boundaries, and a few MeV in the flux rope cores. The X-lines cause strong energy dissipation, which may generate the energetic electron beams around them. The enhanced electron parallel temperature can be caused by the curvature-driven Fermi acceleration and the parallel electric potential. Betatron acceleration due to the magnetic field compression is strong on flux rope boundaries, which enhances energetic electrons in the perpendicular direction. Electrons can be trapped between the flux rope pair due to mirror force and parallel electric potential. Electrostatic structures in the flux rope cores correspond to potential drops up to half of the electron temperature. The energetic electrons and the electron distribution functions in the flux rope cores are suggested to be transported from other dawn-dusk directions, which is a 3-dimensional effect. The acceleration and deceleration of the Betatron and Fermi processes appear alternately indicating that the magnetic field and plasma are turbulent around the flux ropes

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Although the <it>high mobility group A1 </it>(<it>HMGA1</it>) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. <it>HMGA1 </it>functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, <it>HMGA1 </it>is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from <it>HMGA1a </it>transgenic mice at different stages in tumorigenesis.</p> <p>Results</p> <p>RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.</p> <p>Conclusions</p> <p>We found that <it>HMGA1 </it>induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. <it>HMGA1 </it>also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into <it>HMGA1 </it>function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant <it>HMGA1 </it>expression.</p

CONSEQUENCES OF BRCA1 EPIGENETIC SILENCING ON HOMOLOGOUS RECOMBINATION AND DISEASE PROGRESSION IN MYELOID NEOPLASMS

Myeloid malignancies are hematological disorders encompassing chronic myeloid neoplasms to acute leukemias. In recent years, insight from genome-wide discovery studies has improved our understanding and ability to predict prognosis and treatment outcome. Despite these advances, there remains considerable clinical heterogeneity within current classification systems as these diseases often present with diverse and overlapping pathological features. At the same time, there has been limited success in translating these findings into effective therapeutics to improve overall survival. Increasingly, it is recognized that these complex and dynamic molecular changes converge into a small number of biological pathways. Therefore, a pathway-driven approach identifying commonly perturbed processes could yield greater success in developing broadly applicable therapeutics. One promising candidate is the homologous recombination (HR) pathway responsible for repairing double-stranded breaks, since most myeloid neoplasms are characterized by gross chromosomal instability. To objectively assess HR repair in fresh mononuclear cells from myeloid malignancy patients, we developed an ex vivo, short-term assay that determines HR repair based on nuclear RAD51 foci induction after DNA damage. Using this technique, we observed HR defects in 9 of 21 myeloid malignancy samples. Since there is little evidence for mutational alterations in HR genes, we screened HR gene promoters and observed BRCA1 promoter methylation in a significant subpopulation (22/96 samples) that strongly associates with disrupted HR repair. To our knowledge, this is the first report linking BRCA1 methylation to HR defects in patient samples. Next, we validated the patient samples findings by silencing BRCA1 expression in AML cells that recapitulated the HR defects. We treated AML cells with poly(ADP-ribose) polymerase (PARP) inhibitors and observed increased sensitivity with BRCA1 repression, providing a mechanistic justification for previous studies highlighting toxicities with PARP inhibitors in myeloid malignancies. The high prevalence of BRCA1 silencing led us to consider additional roles in driving myeloid disease, as it is known to repress microRNA-155 (miR-155) that is frequently elevated in myeloid malignancies. By correlating gene expression in the patient samples, we found an inverse correlation between BRCA1 and miR-155 levels. miR-155 is frequently elevated in myeloid malignancies and its targets include key regulators of inflammation (SHIP1) and myeloid differentiation (PU.1). Our results here show that BRCA1 loss due to promoter methylation not only contributes to HR defects, but also contributes to disease progression via miR-155 upregulation

Global Hall MHD Simulations of Mercury's Magnetopause Dynamics and FTEs Under Different Solar Wind and IMF Conditions

Mercury possesses a miniature but dynamic magnetosphere driven primarily by the solar wind through magnetic reconnection. A prominent feature of the dayside magnetopause reconnection that has been frequently observed is flux transfer events (FTEs), which are thought to be an important player in driving the global convection at Mercury. Using the BATSRUS Hall magnetohydrodynamics model with coupled planetary interior, we have conducted a series of global simulations to investigate the generation and characteristics of FTEs under different solar wind Alfvenic Mach numbers (M-A) and interplanetary magnetic field (IMF) orientations. An automated algorithm was also developed to consistently identify FTEs and extract their key properties from the simulations. In all simulations driven by steady upstream conditions, FTEs are formed quasi-periodically with recurrence time ranging from 2 to 9 s, and their characteristics vary in time as they evolve and interact with the surrounding plasma and magnetic field. Our statistical analysis of the simulated FTEs reveals that the key properties of FTEs, including spatial size, traveling speed and core field strength, all exhibit notable dependence on the solar wind M-A and IMF orientation, and the trends identified from the simulations are generally consistent with previous MErcury Surface Space ENvironment, GEochemistry, and Ranging observations. It is also found that FTEs formed in the simulations contribute about 313 suggesting that FTEs indeed play an important role in driving the Dungey cycle at Mercury.Peer reviewe