First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). ...We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
•Germline RUNX1 mutations lead to significant phenotypic heterogeneity in families.•Germline RUNX1-mutated acute myeloid leukemia has a different somatic mutation profile from the sporadic RUNX1-mutated type.
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Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia ...pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML.
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•∼50% of the mass of oil left in the Gulf of Mexico has been oxidized to form oxygenated hydrocarbons.•The precursors to the oxidized compounds cannot be elucidated by traditional ...analytical methods.•In the largest study of its kind, we studied the weathered with GCxGC coupled with PLS.•We found candidates for the precursors of oxidized weathering products include saturates.•These results indicate a previously under-reported process in oil spill weathering.
Following the release of crude oil from the Macondo well in 2010, a wide range of weathering processes acted on the spilled oil. A recent study revealed that samples from this spill were oxidized into oxygenated hydrocarbons (OxHC) comprising more than 50% of the extracted hydrocarbons. The precursors of these compounds were not identified despite using a wide range of analytical tools, including gas chromatography (GC). To search for these precursors, over 40 samples were analyzed by comprehensive two-dimensional gas chromatography (GC×GC), one of the largest studies of its kind to date. Partial least squares regression was employed to elucidate the GC×GC peaks that could be the precursors of OxHC in our samples. We found that the formation of OxHC correlated with the disappearance of saturated hydrocarbons, including alkylcyclopentanes, alkyl cyclohexanes, alkylated bicyclic saturated compounds, tricyclic terpanpoids, and alkylbenzenes. These results indicate a previously under-reported chemodynamic process in oil spill weathering.
The ZEB2 transcription factor has been demonstrated to play important roles in hematopoiesis and leukemic transformation. ZEB1 is a close family member of ZEB2 but has remained more enigmatic ...concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between
Zeb1
and
Zeb2
in hematopoietic stem and progenitor cell (HSPC) differentiation, with
Zeb2
being more highly and broadly expressed than
Zeb1
except at a key transition point (short-term HSC ST-HSC➔MPP1), whereby
Zeb1
appears to be the dominantly expressed family member. Inducible genetic inactivation of both
Zeb1
and
Zeb2
using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus–based transgenic models has revealed that
Zeb1
as well as
Zeb2
cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis/splenomegaly and enhance monocyte development. Finally, inactivation of
Zeb2
alone or
Zeb1/2
together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1/2 in AML.
Snail family proteins are key inducers of the epithelial-mesenchymal transition (EMT), a critical process required for normal embryonic development. They have also been strongly implicated in ...regulating the EMT-like processes required for tumour cell invasion, migration, and metastasis. Whether these proteins also contribute to normal blood cell development, however, remains to be clearly defined. Increasing evidence supports a role for the Snail family in regulating cell survival, migration, and differentiation within the haematopoietic system, as well as potentially an oncogenic role in the malignant transformation of haematopoietic stem cells. This review will provide a broad overview of the Snail family, including key aspects of their involvement in the regulation and development of solid organ cancer, as well as a discussion on our current understanding of Snail family function during normal and malignant haematopoiesis.
Prior to Hurricane Isaac making landfall along the Gulf of Mexico coast in August 2012, local and state officials were concerned that the hurricane would mobilize submerged oiled-materials from the ...Deepwater Horizon (DWH) spill. In this study, we investigated materials washed ashore following the hurricane to determine if it affected the chemical composition or density of oil-containing sand patties regularly found on Gulf Coast beaches. While small changes in sand patty density were observed in samples collected before and after the hurricane, these variations appear to have been driven by differences in sampling location and not linked to the passing of Hurricane Isaac. Visual and chemical analysis of sand patties confirmed that the contents was consistent with oil from the Macondo well. Petroleum hydrocarbon signatures of samples collected before and after the hurricane showed no notable changes. In the days following Hurricane Isaac, dark-colored mats were also found on the beach in Fort Morgan, AL, and community reports speculated that these mats contained oil from the DWH spill. Chemical analysis of these mat samples identified n-alkanes but no other petroleum hydrocarbons. Bulk and δ13C organic carbon analyses indicated mat samples were comprised of marshland peat and not related to the DWH spill. This research indicates that Hurricane Isaac did not result in a notable change the composition of oil delivered to beaches at the investigated field sites. This study underscores the need for improved communications with interested stakeholders regarding how to differentiate oiled from non-oiled materials. This is especially important given the high cost of removing oiled debris and the increasing likelihood of false positives as oiled-materials washing ashore from a spill become less abundant over time.
The transcription factor encoded by the E-twenty-six (ETS)-related gene, ERG , is an essential regulator of hematopoietic stem cell function and a potent human oncoprotein. Enforced expression of ERG ...in murine hematopoietic cells leads to the development of a well-characterized lymphoid leukemia and a less well-defined non lymphoid disease. To clarify the latter, we generated murine bone marrow chimeras with enforced Erg expression in engrafted hematopoietic progenitor cells. As expected, these mice developed lymphoid leukemia. However, the previously reported non lymphoid disease that developed was shown to be a uniform, transplantable leukemia with both erythroid and megakaryocytic characteristics. In vivo, this disease had the overall appearance of an erythroleukemia, with an accumulation of immature erythroblasts that infiltrated the bone marrow, spleen, liver, and lung. However, when stimulated in vitro, leukemic cell clones exhibited both erythroid and megakaryocytic differentiation, suggesting that transformation occurred in a bipotential progenitor. Thus, in mice, Erg overexpression induces the development of not only lymphoid leukemia but also erythro-megakaryocytic leukemia.
The Deepwater Horizon oil spill was one of the largest oil spills in history, and the fate of this oil within the Gulf of Mexico ecosystem remains to be fully understood. The goal of this ...study—conducted in mid-June of 2010, approximately two months after the oil spill began—was to understand the key role that microbes would play in the degradation of the oil in the offshore oligotrophic surface waters near the Deepwater Horizon site. As the utilization of organic carbon by bacteria in the surface waters of the Gulf had been previously shown to be phosphorus limited, we hypothesized that bacteria would be unable to rapidly utilize the oil released from the Macondo well. Although phosphate was scarce throughout the sampling region and microbes exhibited enzymatic signs of phosphate stress within the oil slick, microbial respiration within the slick was enhanced by approximately a factor of five. An incubation experiment to determine hydrocarbon degradation rates confirmed that a large fraction of this enhanced respiration was supported by hydrocarbon degradation. Extrapolating our observations to the entire area of the slick suggests that microbes had the potential to degrade a large fraction of the oil as it arrived at the surface from the well. These observations decidedly refuted our hypothesis. However, a concomitant increase in microbial abundance or biomass was not observed in the slick, suggesting that microbial growth was nutrient limited; incubations amended with nutrients showed rapid increases in cell number and biomass, which supported this conclusion. Our study shows that the dynamic microbial community of the Gulf of Mexico supported remarkable rates of oil respiration, despite a dearth of dissolved nutrients.
Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated ...with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(1716)65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(1716)65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.
In spite of significant advancements towards understanding the dynamics of petroleum hydrocarbon degrading microbial consortia, the impacts (direct or indirect via grazing activities) of ...bacterivorous protists remain largely unknown. Microcosm experiments were used to examine whether protistan grazing affects the petroleum hydrocarbon degradation capacity of a deep-sea sediment microbial community from an active Gulf of Mexico cold seep. Differences in n-alkane content between native sediment microcosms and those treated with inhibitors of eukaryotes were assessed by comprehensive two-dimensional gas chromatography following 30–90 day incubations and analysis of shifts in microbial community composition using small subunit ribosomal RNA gene clone libraries. More biodegradation was observed in microcosms supplemented with eukaryotic inhibitors. SSU rRNA gene clone libraries from oil-amended treatments revealed an increase in the number of proteobacterial clones (particularly γ-proteobacteria) after spiking sediments with diesel oil. Bacterial community composition shifted, and degradation rates increased, in treatments where protists were inhibited, suggesting protists affect the hydrocarbon degrading capacity of microbial communities in sediments collected at this Gulf of Mexico site.
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