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HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34 + cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.

In patients who had a relapse of acute myeloid leukemia after allogeneic hematopoietic stem-cell transplantation, no characteristic genetic lesions were detected, but alterations in expression of genes related to immune function were noted, particularly down-regulation of major histocompatibility complex class II genes.

Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D . Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non- TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor. Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones.

We monitored 93 nests of blue-gray gnatcatchers (Polioptila caerulea) from 1995–1997 in east-central Illinois. Habitat selection was assessed at three spatial scales (1 m sphere around nest, 0.005 ha plot and 0.04 ha plot). Leaf density at the 1 m scale was greater at nest sites than non-nest sites. This was the only variable differing between nest sites and paired random sites. Thus, habitat selection was not detected at the larger scales. Overall nest success was 11% (ci 95%: 6–18%); successful nests were significantly higher and farther from habitat edges than unsuccessful nests. Of 36 nests whose contents we could directly observe, 20 (56%) were parasitized by brown-headed cowbirds (Molothrus ater). Gnatcatchers abandoned 16 (80%) parasitized nests during egg-laying or the first 3 d of incubation, whereas only 1 (6%) unparasitized nests were abandoned during these stages. Daily nest success of renests was significantly lower (0.89 ± 0.017) than that of first nests (0.94 ± 0.009). The percentage of successful pairs was 36%. Habitat characteristics at a pair's second nest site were not different from its initial nesting attempt. Lack of specific habitat requirements and persistent renesting may be necessary for this species to achieve reproductive success in this study area.

We monitored 93 nests of blue-gray gnatcatchers (Polioptila caerulea) from 1995-1997 in east-central Illinois. Habitat selection was assessed at three spatial scales (1 m sphere around nest, 0.005 ha plot and 0.04 ha plot). Leaf density at the 1 m scale was greater at nest sites than non-nest sites. This was the only variable differing between nest sites and paired random sites. Thus, habitat selection was not detected at the larger scales. Overall nest success was 11% (CI 95%: 6-18%); successful nests were significantly higher and farther from habitat edges than unsuccessful nests. Of 36 nests whose contents we could directly observe, 20 (56%) were parasitized by brown-headed cowbirds (Molothrus ater). Gnatcatchers abandoned 16 (80%) parasitized nests during egg-laying or the first 3 d of incubation, whereas only 1 (6%) unparasitized nests were abandoned during these stages. Daily nest success of renests was significantly lower (0.89 plus or minus 0.017) than that of first nests (0.94 plus or minus 0.009). The percentage of successful pairs was 36%. Habitat characteristics at a pair's second nest site were not different from its initial nesting attempt. Lack of specific habitat requirements and persistent renesting may be necessary for this species to achieve reproductive success in this study area.

Acute myeloid leukemia (AML) patients rarely have long first remissions (> 5 years) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, short remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA sequencing and functional immunologic studies, we characterized 28 Normal Karyotype (NK)-AML patients with >5 year first remissions after chemotherapy (Long First Remissions, LFR) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 years (Standard First Remissions, SFR). Our combined analyses indicated that genetic risk profiling at presentation (as defined by ELN 2017 Criteria) was not sufficient to explain the outcomes of many SFR cases. Single cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T-cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells, or blocking the inhibitory MHC Class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ Tcell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy. Competing Interest Statement The authors have declared no competing interest.

Several theories have been proposed to describe the formation of black hole seeds in the early Universe and to explain the emergence of very massive black holes observed in the first thousand million years after the Big Bang 1 – 3 . Models consider different seeding and accretion scenarios 4 – 7 , which require the detection and characterization of black holes in the first few hundred million years after the Big Bang to be validated. Here we present an extensive analysis of the JWST-NIRSpec spectrum of GN-z11, an exceptionally luminous galaxy at z  = 10.6, revealing the detection of the [Ne iv ] λ 2423 and CII* λ 1335 transitions (typical of active galactic nuclei), as well as semi-forbidden nebular lines tracing gas densities higher than 10 9  cm −3 , typical of the broad line region of active galactic nuclei. These spectral features indicate that GN-z11 hosts an accreting black hole. The spectrum also reveals a deep and blueshifted CIV λ 1549 absorption trough, tracing an outflow with velocity 800−1,000 km s −1 , probably driven by the active galactic nucleus. Assuming local virial relations, we derive a black hole mass of log ( M BH / M ⊙ ) = 6.2 ± 0.3 , accreting at about five times the Eddington rate. These properties are consistent with both heavy seeds scenarios and scenarios considering intermediate and light seeds experiencing episodic super-Eddington phases. Our finding explains the high luminosity of GN-z11 and can also provide an explanation for its exceptionally high nitrogen abundance. An extensive analysis of the JWST-NIRSpec spectrum of GN-z11 shows a supermassive black hole of a few million solar masses in a galaxy 440 million years after the Big Bang.

Cosmic reionization began when ultraviolet (UV) radiation produced in the first galaxies began illuminating the cold, neutral gas that filled the primordial Universe 1 , 2 . Recent James Webb Space Telescope (JWST) observations have shown that surprisingly UV-bright galaxies were in place beyond redshift z  = 14, when the Universe was less than 300 Myr old 3 , 4 – 5 . Smooth turnovers of their UV continua have been interpreted as damping-wing absorption of Lyman-α (Ly-α), the principal hydrogen transition 6 , 7 , 8 – 9 . However, spectral signatures encoding crucial properties of these sources, such as their emergent radiation field, largely remain elusive. Here we report spectroscopy from the JWST Advanced Deep Extragalactic Survey (JADES 10 ) of a galaxy at redshift z  = 13.0 that reveals a singular, bright emission line unambiguously identified as Ly-α, as well as a smooth turnover. We observe an equivalent width of EW Ly-α  > 40 Å (rest frame), previously only seen at z  < 9 where the intervening intergalactic medium becomes increasingly ionized 11 . Together with an extremely blue UV continuum, the unexpected Ly-α emission indicates that the galaxy is a prolific producer and leaker of ionizing photons. This suggests that massive, hot stars or an active galactic nucleus have created an early reionized region to prevent complete extinction of Ly-α, thus shedding new light on the nature of the earliest galaxies and the onset of reionization only 330 Myr after the Big Bang. Spectroscopy from the JWST Advanced Deep Extragalactic Survey of a galaxy at redshift 13 shows a singular, bright emission line identified as Lyman-α, suggesting the onset of reionization only 330 Myr after the Big Bang.

The first observations of the James Webb Space Telescope (JWST) have revolutionized our understanding of the Universe by identifying galaxies at redshift z  ≈ 13 (refs. 1 , 2 – 3 ). In addition, the discovery of many luminous galaxies at Cosmic Dawn ( z  > 10) has suggested that galaxies developed rapidly, in apparent tension with many standard models 4 , 5 , 6 , 7 – 8 . However, most of these galaxies lack spectroscopic confirmation, so their distances and properties are uncertain. Here we present JWST Advanced Deep Extragalactic Survey–Near-Infrared Spectrograph spectroscopic confirmation of two luminous galaxies at z = 14.32 − 0.20 + 0.08 and z  = 13.90 ± 0.17. The spectra reveal ultraviolet continua with prominent Lyman-α breaks but no detected emission lines. This discovery proves that luminous galaxies were already in place 300 million years after the Big Bang and are more common than what was expected before JWST. The most distant of the two galaxies is unexpectedly luminous and is spatially resolved with a radius of 260 parsecs. Considering also the very steep ultraviolet slope of the second galaxy, we conclude that both are dominated by stellar continuum emission, showing that the excess of luminous galaxies in the early Universe cannot be entirely explained by accretion onto black holes. Galaxy formation models will need to address the existence of such large and luminous galaxies so early in cosmic history. JWST–NIRSpec spectroscopic confirmation of two luminous galaxies is presented, proving that luminous galaxies were already in place 300 million years after the Big Bang and are more common than what was expected before JWST.

For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10−16) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. National Heart, Lung, and Blood Institute, National Institutes of Health.