Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A ...(MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with the most subtype-specific increase in expression, LOC100289656, and identified cryptic MLL fusions, including a new MLL-ENAH fusion. We also identified a subset of MLL fusion specimens carrying mutations in SPI1 accompanied by inactivation of its transcriptional network, as well as frequent RAS pathway mutations, which sensitized the leukemias to synthetic lethal interactions between MEK and receptor tyrosine kinase inhibitors. This transcriptomics-based characterization and chemical interrogation of human MLL-rearranged AML was a valuable approach for identifying complementary features that define this disease.
In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPAbi) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) ...specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease.
•CSF3R was the most frequently mutated gene identified in this CEBPAbi AML cohort analyzed by next-generation sequencing.•CEBPAbi AML that have a characteristic transcriptomic profile are more sensitive to JAK inhibitors than CEBPAwt AML.
The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 ...EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34+ cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.
•EVI1-r AMLs have recurrent mutations in RAS and other signaling genes, splicing factors, and at a lower frequency, IKZF1 and TP53.•EVI1-r AMLs show a characteristic transcriptome profile marked by high expression of MECOM, PREX2, MYCT1, PAWR, and VIP.
Based on transcriptomic analyses of thousands of samples from The Cancer Genome Atlas, we report that expression of constitutive proteasome (CP) genes (PSMB5, PSMB6, PSMB7) and immunoproteasome (IP) ...genes (PSMB8, PSMB9, PSMB10) is increased in most cancer types. In breast cancer, expression of IP genes was determined by the abundance of tumor infiltrating lymphocytes and high expression of IP genes was associated with longer survival. In contrast, IP upregulation in acute myeloid leukemia (AML) was a cell-intrinsic feature that was not associated with longer survival. Expression of IP genes in AML was IFN-independent, correlated with the methylation status of IP genes, and was particularly high in AML with an M5 phenotype and/or MLL rearrangement. Notably, PSMB8 inhibition led to accumulation of polyubiquitinated proteins and cell death in IP
but not IP
AML cells. Co-clustering analysis revealed that genes correlated with IP subunits in non-M5 AMLs were primarily implicated in immune processes. However, in M5 AML, IP genes were primarily co-regulated with genes involved in cell metabolism and proliferation, mitochondrial activity and stress responses. We conclude that M5 AML cells can upregulate IP genes in a cell-intrinsic manner in order to resist cell stress.
Temperatures in the arctic and subarctic are rising at more than twice the rate of the global average, driving the accelerated thawing of permafrost across the region. The impacts of permafrost ...degradation have been studied in the discontinuous permafrost zone at Umiujaq, in northern Quebec, Canada, for over 30 years, but the effects of changing land cover on groundwater recharge are not well understood. The water table fluctuation method was used to compute groundwater recharge using 4 years of water level data and soil moisture readings from five field sites characteristic of different stages of permafrost degradation and vegetation invasion. Results indicate that as vegetation grows taller, groundwater recharge increases, likely due to increased snow thickness. Results were then combined with a preexisting conceptual model that describes the evolution from tundra to shrubland and forests to create a new model for describing how groundwater recharge is affected by landscape evolution.
Plain language summary
Thawing permafrost (ground that is below 0°C for at least 2 years) allows for vegetation to grow in areas where growth was not previously possible. This paper examines how different types of vegetation affect the ability of water to infiltrate the soil and flow toward the water table, a process called groundwater recharge. Using field data from five typical types of vegetation in the discontinuous permafrost zone in northern Quebec, Canada, we estimated how much groundwater recharge occurred under these different types of vegetation: tundra/permafrost mound, lichens and herbs, lichens and low shrubs, medium shrubs, and trees. Based on the results, as the plants grow larger, more groundwater recharge is possible. This increase in recharge occurs because taller plants trap more snow in winter, resulting in the production of more meltwater in spring. We then combine our results with the findings from another study in the same area, which stated that the five types of land cover represent a model for how the landscape will change as the permafrost thaws. Our new combined model allows for the estimation of how groundwater recharge will change as a result of permafrost thaw and ecological change.
Key Points
Increased landcover height appears positively correlated with increased recharge
As land cover increases in height, the date of the first recharge event in a given hydrologic year moves later into the summer
Increased recharge is driven by greater snow thickness and prolonged snowmelt due to snow entrapment and shading under taller land cover
Rising temperatures in the Arctic and subarctic are driving the rapid thaw of permafrost by reducing permafrost cooling, increasing active layer thickness, and promoting talik formation. In this ...study, the cyrohydrogeology of a permafrost mound located within the discontinuous permafrost zone near Umiujaq (Nunavik, Québec, Canada) is characterized through the analysis of a dataset covering more than two decades of monitoring. This dataset captures a high degree of interannual variability in air temperature and ground thermal conditions, as well as the formation and closure of a supra‐permafrost talik. Data indicate that variable saturation and advective heat transport directly contribute to the expansion and contraction of the talik. Data further indicate the presence of two distinct thermo‐hydrologic settings resulting from differences in surface conditions, as well as subsurface thermal and flow regimes. The first, found at the top of the mound feature, is characterized by very low moisture contents (<0.05 m3/m3), while the second, found at the side of the mound feature, shows higher annual moisture contents that strongly influence the dynamics of heat and groundwater flow. The data were synthesized into a detailed conceptual model of the cyrohydrogeological dynamics that highlights the important role of hydrogeological characterization and long‐term data sets in understanding the effects of groundwater flow on seasonal frost and permafrost dynamics. Specifically, the results presented here show that in the absence of long‐term data sets, longer‐period transient phenomena such as talik opening and closure may be misrepresented as uni‐directional feedback loops, as opposed to highly dynamic temporary phenomena.
Plain Language Summary
Global warming is causing widespread permafrost (ground that remains below 0°C annually) thaw in Arctic and subarctic environments. Because the presence or absence of permafrost has important implications for local ecology, hydrology, and geomorphology, understanding how the permafrost is changing, and the effects of these changes, is needed to ensure sustainable development in local communities and to protect the environment. However, the data required to understand permafrost thaw (such as subsurface temperature and water content) are often unavailable, as performing fieldwork in these regions is difficult and expensive. As a result, computer simulations used to forecast permafrost thaw generally consider “ideal” conditions and may omit important processes, such as groundwater flow or the role of unsaturated soil. This study uses an extensive network of field instruments located near the Inuit community of Umiujaq (Nunavik, Québec, Canada) to perform a detailed characterization of a thawing permafrost mound in order to investigate the effects of varying topography, vegetation, and snow cover on permafrost and seasonal frost extents. The resulting dataset spans more than 20 years and allows for a more complete understanding of the role of soil moisture and groundwater on the thermal dynamics of permafrost in variably saturated environments.
Key Points
Talik opening and closure is observed through long‐term, high‐resolution monitoring of a degrading permafrost mound
Soil moisture, advective heat transport, and high interannual air temperature variability control seasonal frost and talik dynamics
Subsurface thermal and flow regimes in variably saturated mineral soils are synthesized in a unifying conceptual model of a permafrost mound
Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy, which is initiated and driven by a rare fraction of leukemia stem cells (LSCs). Despite the difficulties of ...identifying a common LSC phenotype, there is increasing evidence that high expression of stem cell gene signatures is associated with poor clinical outcome. Identification of functionally distinct subpopulations in this disease is therefore crucial to dissecting the molecular machinery underlying LSC self-renewal. Here, we combined next-generation sequencing technology with in vivo assessment of LSC frequencies and identified the adhesion G protein–coupled receptor 56 (GPR56) as a novel and stable marker for human LSCs for the majority of AML samples. High GPR56 expression was significantly associated with high-risk genetic subgroups and poor outcome. Analysis of GPR56 in combination with CD34 expression revealed engraftment potential of GPR56+ cells in both the CD34− and CD34+ fractions, thus defining a novel LSC compartment independent of the CD34+CD38− LSC phenotype.
•GPR56 is a novel LSC marker for the majority of AML samples.•GPR56 expression levels correlate with genetic risk groups and clinical outcome in AML.
FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon cooccurrence. Here we ...show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia-specific GPR56highCD34low immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC marker GPR56 allowed isolation of triple-mutated from DNMT3A/NPM1 double-mutated subclones. Moreover, in DNMT3A R882-mutated patients, CpG hypomethylation at the HLF transcription start site correlated with high HLF mRNA expression, which was itself associated with poor survival. Loss of HLF via CRISPR/Cas9 significantly reduced the CD34+GPR56+ LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when reintroduced in culture. RNA sequencing of primary human triple-mutated AML cells after shRNA-mediated HLF knockdown revealed the NOTCH target Hairy and Enhancer of Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel targets of HLF, potentially mediating these effects. Overall, our data establish HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.
•HLF is overexpressed in normal karyotype AML triple mutated for NPM1, DNMT3A, and FLT3–internal tandem duplication (ITD).•Loss of HLF reduces the CD34+GPR56+ compartment, accelerates cell cycle progression, and decreases HES1 and CDKN1C expression.
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Abstract
MHC-I-associated peptides deriving from non-coding genomic regions and mutations can generate tumor-specific antigens, including neoantigens. Quantifying tumor-specific antigens’ RNA ...expression in malignant and benign tissues is critical for discriminating actionable targets. We present BamQuery, a tool attributing an exhaustive RNA expression to MHC-I-associated peptides of any origin from bulk and single-cell RNA-sequencing data. We show that many cryptic and mutated tumor-specific antigens can derive from multiple discrete genomic regions, abundantly expressed in normal tissues. BamQuery can also be used to predict MHC-I-associated peptides immunogenicity and identify actionable tumor-specific antigens de novo.
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