Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML

Resilience of a tropical sport fish population to a severe cold event varies across five estuaries in southern Florida

For species that are closely managed, understanding population resilience to environmental and anthropogenic disturbances (i.e., recovery trajectories across broad spatial areas) can guide which suite of management actions are available to mitigate any impacts. During January 2010, an extreme cold event in south Florida caused widespread mortality of common snook, Centropomus undecimalis, a popular sport fish. Interpretation of trends using fishery-independent monitoring data in five south Florida estuaries showed that changes in catch rates of adult snook (\u3e500 mm standard length) varied between no effects postevent to large effects and 4-yr recoveries. The reasons for the variation across estuaries are unknown, but are likely related to differences in estuary geomorphology and habitat availability (e.g., extent of deep rivers and canals) and differences in the proportions of behavior contingents (i.e., segments of the population that use divergent movement tactics) that place snook in different areas of the estuary during winter. Emerging awareness of the presence of behavior contingents, identification of overwintering sites, and improvements of abundance indices in remote nursery habitats should provide a better understanding of population resilience to disturbance events for snook. Given that changes in the frequency of short-lived, severe cold events are currently unknown, the findings and management actions described here for a tropical species living at the edge of its distribution should be useful to scientists forecasting the effects of climate change

Active restructuring of cytoskeleton composites leads to increased mechanical stiffness, memory, and heterogeneity

The composite cytoskeleton, comprising interacting networks of semiflexible actin and rigid microtubules, actively generates forces and restructures using motor proteins such as myosins to enable key mechanical processes including cell motility and mitosis. Yet, how motor-driven activity alters the mechanics of cytoskeleton composites remains an open challenge. Here, we perform optical tweezers microrheology on actin-microtubule composites driven by myosin II motors to show that motor activity increases the linear viscoelasticity and elastic storage of the composite by active restructuring to a network of tightly-packed filament clusters and bundles. Our nonlinear microrheology measurements performed hours after cessation of activity show that the motor-contracted structure is stable and robust to nonlinear forcing. Unique features of the nonlinear response include increased mechanical stiffness, memory and heterogeneity, coupled with suppressed filament bending following motor-driven restructuring. Our results shed important new light onto the interplay between viscoelasticity and non-equilibrium dynamics in active polymer composites such as the cytoskeleton

Discovery and Use of a Natural Mutation that Results in Severe Combined Immuno Deficiency in Pigs

Piglets from the low residual feed intake (RFI) line at ISU were found to be affected with a lethal autosomal recessive mutation that causes Severe Combined Immunodeficiency (SCID). Bone marrow allotransplantation rescued the immune deficiency in four of nine attempted transfers; the other five exhibited signs of severe graft versus host disease and were euthanized. A genome wide association study identified a 5.6 Mb region that contained the causative mutation. Affected haplotypes were traced back to the founders of the RFI population, who were sourced from the purebred Yorkshire population. The SCID pigs will be useful as a biomedical model, as pigs are anatomically and genetically more similar to humans than SCID mice, which are now widely used. Development of a genetic test for the causative mutation will be valuable to the swine industry, allowing breeders to identify carriers

The Genomic Health of Human Pluripotent Stem Cells: Genomic Instability and the Consequences on Nuclear Organization

Human pluripotent stem cells (hPSCs) are increasingly used for cell-based regenerative therapies worldwide, with embryonic and induced pluripotent stem cells as potential treatments for debilitating and chronic conditions, such as age-related macular degeneration, Parkinson's disease, spinal cord injuries, and type 1 diabetes. However, with the level of genomic anomalies stem cells generate in culture, their safety may be in question. Specifically, hPSCs frequently acquire chromosomal abnormalities, often with gains or losses of whole chromosomes. This review discusses how important it is to efficiently and sensitively detect hPSC aneuploidies, to understand how these aneuploidies arise, consider the consequences for the cell, and indeed the individual to whom aneuploid cells may be administered

Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Control in Hypertension

Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1⁻4 as most to least likely to respond based on the algorithmic assessment of individual patient's genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.Geneticure Inc.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]