JAK2 Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies

published: 12 July 2022Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 (JAK2) correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating JAK2 point mutations and JAK2 fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific JAK2 lesions. This review focuses on the molecular mechanisms behind ALL-associated JAK2 mutations and JAK2 fusion genes, known and potential causes of JAK-inhibitor resistance, and how JAK2 alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.Charlotte EJ. Downes, Barbara J. McClure, Daniel P. McDougal, Susan L. Heatley, John B. Bruning, Daniel Thomas, David T. Yeung and Deborah L. Whit

Shannon Information Theory and Molecular Biology

The role and the contribution of Shannon Information Theory to the development of Molecular Biology has been the object of stimulating debates during the last thirty years. This seems to be connected with some semantic charms associated with the use of the word \u201cinformation\u201d in the biological context. Furthermore information itself, if viewed in a broader perspective, is far from being completely defined in a fashion that overcomes the technical level at which the classical Information Theory has been conceived. This review aims at building on the acknowledged contribution of Shannon Information Theory to Molecular Biology, so as to discover if it is only a technical tool to analyze DNA and proteinic sequences, or if it can rise, at least in perspective, to a higher role that exerts an influence on the construction of a suitable model for handling the genetic information in Molecular Biology

Search for Tensor, Vector, and Scalar Polarizations in the Stochastic Gravitational-Wave Background

The detection of gravitational waves with Advanced LIGO and Advanced Virgo has enabled novel tests of general relativity, including direct study of the polarization of gravitational waves. While general relativity allows for only two tensor gravitational-wave polarizations, general metric theories can additionally predict two vector and two scalar polarizations. The polarization of gravitational waves is encoded in the spectral shape of the stochastic gravitational-wave background, formed by the superposition of cosmological and individually unresolved astrophysical sources. Using data recorded by Advanced LIGO during its first observing run, we search for a stochastic background of generically polarized gravitational waves. We find no evidence for a background of any polarization, and place the first direct bounds on the contributions of vector and scalar polarizations to the stochastic background. Under log-uniform priors for the energy in each polarization, we limit the energy densities of tensor, vector, and scalar modes at 95% credibility to Ω0T<5.58×10-8, Ω0V<6.35×10-8, and Ω0S<1.08×10-7 at a reference frequency f0=25 Hz. © 2018 American Physical Society

On the progenitor of binary neutron star merger GW170817

On 2017 August 17 the merger of two compact objects with masses consistent with two neutron stars was discovered through gravitational-wave (GW170817), gamma-ray (GRB 170817A), and optical (SSS17a/AT 2017gfo) observations. The optical source was associated with the early-type galaxy NGC 4993 at a distance of just ∼40 Mpc, consistent with the gravitational-wave measurement, and the merger was localized to be at a projected distance of ∼2 kpc away from the galaxy's center. We use this minimal set of facts and the mass posteriors of the two neutron stars to derive the first constraints on the progenitor of GW170817 at the time of the second supernova (SN). We generate simulated progenitor populations and follow the three-dimensional kinematic evolution from binary neutron star (BNS) birth to the merger time, accounting for pre-SN galactic motion, for considerably different input distributions of the progenitor mass, pre-SN semimajor axis, and SN-kick velocity. Though not considerably tight, we find these constraints to be comparable to those for Galactic BNS progenitors. The derived constraints are very strongly influenced by the requirement of keeping the binary bound after the second SN and having the merger occur relatively close to the center of the galaxy. These constraints are insensitive to the galaxy's star formation history, provided the stellar populations are older than 1 Gyr

Constraints on cosmic strings using data from the first Advanced LIGO observing run

Cosmic strings are topological defects which can be formed in grand unified theory scale phase transitions in the early universe. They are also predicted to form in the context of string theory. The main mechanism for a network of Nambu-Goto cosmic strings to lose energy is through the production of loops and the subsequent emission of gravitational waves, thus offering an experimental signature for the existence of cosmic strings. Here we report on the analysis conducted to specifically search for gravitational-wave bursts from cosmic string loops in the data of Advanced LIGO 2015-2016 observing run (O1). No evidence of such signals was found in the data, and as a result we set upper limits on the cosmic string parameters for three recent loop distribution models. In this paper, we initially derive constraints on the string tension Gμ and the intercommutation probability, using not only the burst analysis performed on the O1 data set but also results from the previously published LIGO stochastic O1 analysis, pulsar timing arrays, cosmic microwave background and big-bang nucleosynthesis experiments. We show that these data sets are complementary in that they probe gravitational waves produced by cosmic string loops during very different epochs. Finally, we show that the data sets exclude large parts of the parameter space of the three loop distribution models we consider

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

HearNPV susceptibility in Helicoverpa armigera and Helicoverpa punctigera strains resistant to Bt toxins Cry1Ac, Cry2Ab, and Vip3Aa

Genetically engineered crops expressing insecticidal toxins from Bacillus thuringiensis (Bt) have improved the management of targeted lepidopteran pests and reduced the use of insecticide sprays. These benefits explain an increasing adoption of Bt crops worldwide, intensifying the selection pressure on target species and the risk of resistance. Nucleopolyhedroviruses (NPVs) are effective bioinsecticides against numerous important lepidopteran pests. If Bt-resistant insects are shown to be susceptible to NPVs then these bioinsecticides could be a valuable component of Insecticide Resistance Management (IRM) strategies for Bt crops. We assessed the effectiveness of a Helicoverpa nucleopolyhedrovirus (HearNPV) against several different Bt-resistant strains. Utilising a droplet feeding bioassay we confirmed susceptibility to HearNPV in Helicoverpa punctigera and Helicoverpa armigera larvae resistant to the Bt toxins Cry1Ac, Cry2Ab, and Vip3A. Dual resistant H. punctigera, (Cry1Ac/Cry2Ab, and Cry2Ab/Vip3A) and dual resistant H. armigera (Cry2Ab/Vip3A) were also susceptible to HearNPV. Regardless of their specific resistance profile, Bt-resistant larvae displayed statistically similar lethal concentration (LC50) and lethal time (LT50) responses to HearNPV when compared to Bt-sensitive control insects. These results indicate that Bt-resistant H. armigera and H. punctigera are not cross-resistant to HearNPV. Consequently, the use of HearNPV against these pests may be a valuable tool to an IRM strategy for controlling Bt-resistant populations

Inherited missense variants that affect GFI1B function do not necessarily cause bleeding diatheses

Contains fulltext : 206781.pdf (publisher's version ) (Open Access

Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis

10.7554/eLife.40811eLife8e4081