Mining the literature for genes associated with placenta-mediated maternal diseases.

Automated literature analysis could significantly speed up understanding of the role of the placenta and the impact of its development and functions on the health of the mother and the child. To facilitate automatic extraction of information about placenta-mediated disorders from the literature, we manually annotated genes and proteins, the associated diseases, and the functions and processes involved in the development and function of placenta in a collection of PubMed/MEDLINE abstracts. We developed three baseline approaches to finding sentences containing this information: one based on supervised machine learning (ML) and two based on distant supervision: 1) using automated detection of named entities and 2) using MeSH. We compare the performance of several well-known supervised ML algorithms and identify two approaches, Support Vector Machines (SVM) and Generalized Linear Models (GLM), which yield up to 98% recall precision and F1 score. We demonstrate that distant supervision approaches could be used at the expense of missing up to 15% of relevant documents.

Information Needs in the Precision Medicine Era: How Genetics Home Reference Can Help.

Precision medicine focuses on understanding individual variability in disease prevention, care, and treatment. The Precision Medicine Initiative, launched by President Obama in early 2015, aims to bring this approach to all areas of health care. However, few consumer-friendly resources exist for the public to learn about precision medicine and the conditions that could be affected by this approach to care. Genetics Home Reference, a website from the US National Library of Medicine, seeks to support precision medicine education by providing the public with summaries of genetic conditions and their associated genes, as well as information about issues related to precision medicine such as disease risk and pharmacogenomics. With the advance of precision medicine, consumer-focused resources like Genetics Home Reference can be foundational in providing context for public understanding of the increasing amount of data that will become available.

Defective nonhomologous end joining blocks B-cell development in FLT3/ITD mice.

We have generated an FLT3/ITD knock-in mouse model in which mice with an FLT3/ITD mutation develop myeloproliferative disease (MPD) and a block in early B-lymphocyte development. To elucidate the role of FLT3/ITD signaling in B-cell development, we studied VDJ recombination in the pro-B cells of FLT3/ITD mice and discovered an increased frequency of DNA double strand breaks (DSBs) introduced by the VDJ recombinase. Early pro-B cells from FLT3/ITD mice were found to have a lower efficiency and decreased accuracy of DSB repair by nonhomologous end joining (NHEJ), which is required for rejoining DSBs during VDJ recombination. Reduced NHEJ repair probably results from reduced expression of Ku86, a key component of the classic DNA-PK-dependent NHEJ pathway. In compensation, early pro-B cells from FLT3/ITD cells mice show increased levels of the alternative, and highly error-prone, NHEJ pathway protein PARP1, explaining the increase in repair errors. These data suggest that, in early pro-B cells from FLT3/ITD mice, impairment of classic NHEJ decreases the ability of cells to complete postcleavage DSB ligation, resulting in failure to complete VDJ recombination and subsequent block of B-lymphocyte maturation. These findings might explain the poor prognosis of leukemia patients with constitutive activation of FLT3 signaling.

Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.

Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) by internal tandem duplication (ITD) mutations is one of the most common molecular alterations known in acute myeloid leukemia (AML). To investigate the role FLT3/ITD mutations play in the development of leukemia, we generated a FLT3/ITD knock-in mouse model by inserting an ITD mutation into the juxtamembrane domain of murine Flt3. FLT3wt/ITD mice developed myeloproliferative disease, characterized by splenomegaly, leukocytosis, and myeloid hypercellularity, which progressed to mortality by 6 to 20 months. Bone marrow (BM) and spleen from FLT3wt/ITD mice had an increased fraction of granulocytes/monocytes and dendritic cells, and a decreased fraction of B-lymphocytes. No sign of acute leukemia was observed over the lifetime of these mice. BM from FLT3wt/ITD mice showed enhanced potential to generate myeloid colonies in vitro. BM from FLT3wt/ITD mice also produced more spleen colonies in the in vivo colony-forming unit (CFU)-spleen assay. In the long-term competitive repopulation assay, BM cells from FLT3wt/ITD mice outgrew the wild-type competitor cells and showed increased myeloid and reduced lymphoid expansion activity. In summary, our data indicate that expression of FLT3/ITD mutations alone is capable of conferring normal hematopoietic stem/progenitor cells (HSPCs) with enhanced myeloid expansion. It also appears to suppress B lymphoid maturation. Additional cooperative events appear to be required to progress to acute leukemia.