Key Points• GATA1 mutations are common in neonates with Down syndrome but are often unsuspected and detectable only with sensitive methods.• Multilineage blood abnormalities in all Down syndrome neonates in the absence of GATA1 mutations suggests that trisomy 21 itself perturbs hemopoiesis.Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis.To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore lowabundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity ∼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones. (Blood. 2013;122(24):3908-3917)

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the most established and commonly used cellular immunotherapy in cancer care. It is the most potent anti-leukemic therapy in patients with acute myeloid leukemia (AML) and is routinely used with curative intent in patients with intermediate and poor risk disease. Donor T cells, and possibly other immune cells, eliminate residual leukemia cells after prior (radio)chemotherapy. This immune-mediated response is known as graft-versus-leukemia (GvL). Donor alloimmune responses can also be directed against healthy tissues, which is known as graft-versus-host disease (GvHD). GvHD and GvL often co-occur and, therefore, a major barrier to exploiting the full immunotherapeutic benefit of donor immune cells against patient leukemia is the immunosuppression required to treat GvHD. However, curative responses to allo-SCT and GvHD do not always occur together, suggesting that these two immune responses could be de-coupled in some patients. To make further progress in successfully promoting GvL without GvHD, we must transform our limited understanding of the cellular and molecular basis of GvL and GvHD. Specifically, in most patients we do not understand the antigenic basis of immune responses in GvL and GvHD. Identification of antigens important for GvL but not GvHD, and vice versa, could impact on donor selection, allow us to track GvL immune responses and begin to specifically harness and strengthen anti-leukemic immune responses against patient AML cells, whilst minimizing the toxicity of GvHD.

Acute erythroleukemia (AML-M6 or AEL) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing three genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (e.g. DNMT3A, TET2 or IDH2), and undefined cases with low mutational burden. We established an erythroid vs. myeloid transcriptomics-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, more than 25% of AEL patients, including in the genetically-undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1 binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicates that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.

Highlights d Biallelic C/EBPa and GATA-2 ZnF1 mutations synergize during leukemogenesis d GATA-2 ZnF1 mutation generates an erythroid-permissive chromatin state d C/EBPa and GATA-2 mutant NMPs show ectopic erythroid lineage potential d Transformed leukemic NMPs are bipotent neutrophilerythroid leukemia-initiating cells

Background Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)‐based studies. Objectives To assess for an association between clinically validated TTS and COVID‐19 vaccination. Methods We used the self‐controlled case series method to assess the risks of clinically validated acute TTS after a first COVID‐19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02‐31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18‐ to 39‐year‐olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4‐ to 27‐ and 28‐ to 41‐day periods (RI, 1.52; 95% CI, 0.88‐2.63; and (RI, 1.70; 95% CI, 0.73‐3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS‐CoV‐2 test occurred across all age groups and exposure periods. Conclusions We demonstrate an increased risk of TTS in the 4 to 27 days following COVID‐19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS‐CoV‐2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

Red cells play a key role in normal haemostasis in vitro but their importance clinically is less clear. The objective of this meta-analysis was to assess if correction of anaemia by transfusing red cells at a high haemoglobin threshold (liberal transfusion) is superior to transfusion at a lower haemoglobin threshold (restrictive transfusion) for reducing the risk of bleeding or thrombotic events. We searched for randomised controlled trials in any clinical setting that compared two red cell transfusion thresholds and investigated the risk of bleeding. We searched for studies published up to October 19, 2016 in The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, and the Transfusion Evidence Library and ISI Web of Science. Relative risks (RR) or Peto Odds Ratios (pOR) were pooled using a random-effect model. Nineteen randomised trials with 9852 participants were eligible for inclusion in this review. Overall there was no difference in the risk of any bleeding between transfusion strategies (RR 0.91, 95 % confidence interval [CI] 0.74 to 1.12). The risk of severe or life-threatening bleeding was lower with a restrictive strategy (RR 0.75, 95 % CI 0.57 to 0.99). There was no difference in the risk of thrombotic events (RR 0.83, 95 % CI 0.61 to 1.13). The risk of any bleeding was not reduced with liberal transfusion and there was no overall difference in the risk of thrombotic events. Data from the included trials do not support aiming for a high haemoglobin threshold to improve haemostasis. PROSPERO registration number CRD42016035519.

Hillsborough High School's iSTEM club has been designing and building a quadcopter from component parts.

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