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Germline SAMD9 and SAMD9L mutations ( SAMD9/9L mut ) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort ( n  = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9L mut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L mut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9L mut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L mut suppressed HEK293 cell growth, and mutations expressed in CD34 +  cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L mut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9L mut ). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L mut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome.

A new high-resolution deglacial and Holocene sea surface temperature (SST) reconstruction is presented for the Alboran Sea (western Mediterranean), based on Mg∕Ca ratios measured in the planktonic foraminifera Globigerina bulloides. This new record is evaluated by comparison with other Mg∕Ca SST records and previously published alkenone SST reconstructions from the same region for both the Holocene and glacial periods. In all cases there is a high degree of coherence between the different Mg∕Ca SST records but strong discrepancies when compared to the alkenone SST records. We argue that these discrepancies are due to differences in the proxy response during deglaciation which we hypothesize to reflect a resilience strategy of G. bulloides, changing its main growth season, and consequently Mg∕Ca records a shorter deglacial warming than alkenones. In contrast, short-term Holocene SST variability is larger in the Mg∕Ca SST than in the alkenone SST records. We propose that the larger Mg∕Ca SST variability is a result of spring temperatures variability, while the smoothed alkenone SST variability represents averaged annual temperatures. The Mg∕Ca SST record differentiates the Holocene into three periods: (1) the warmest SST values occurred during the Early Holocene (11.7–9 cal. kyr BP), (2) a continuous cooling trend occurred during the Middle Holocene that culminated in the coldest Holocene SST having a double cold peak structure centred at around 4.2 cal. kyr BP, and (3) the Late Holocene (4.2 cal. kyr BP to present) did not follow any clear cooling/warming trend although millennial-scale oscillations were enhanced. This SST evolution is discussed in the context of the changing properties in the Atlantic inflow water associated with North Atlantic circulation conditions and also with local hydrographical and atmospheric changes. We propose that a tight link between North Atlantic circulation patterns and the inflow of surface waters into the Mediterranean played a major role in controlling Holocene climatic variability of this region.

Chimeric antigen receptor (CAR)T-cell CD19 therapy is an effective treatment for relapsed/refractory B-cell acute lymphoblastic leukemia. It can be associated with life-threatening toxicities which often require PICU admission. Purpose: to describe clinical characteristics, treatment and outcome of these patients. Prospective observational cohort study conducted in a tertiary pediatric hospital from 2016-2021. Children who received CAR-T admitted to PICU were included. We collected epidemiological, clinical characteristics, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), treatment, length of stay and mortality. CAR T-cells (4-1BB constructs) were infused in 59 patients. Twenty-four (40.7%) required PICU admission, length of stay was 4 days (IQR 3-6). Median age was 8.3 years (range 4-24). Patients admitted to PICU presented higher disease burden before infusion: 24% blasts in bone marrow (IQR 5-72) vs. 0 (0-6.9), p<0.001. No patients with <5% blasts were admitted to PICU. Main reasons for admissions were CRS (n=20, 83.3%) and ICANS (n=3, 12.5%). Fourteen patients (58.3%) required inotropic support, 14(58.3%) respiratory. Sixteen patients (66.6%) received tocilizumab, 10(41.6%) steroids, 6(25.0%) anakinra, and 5(20.8%) siltuximab. Ten patients (41.6%) presented neurotoxicity, six of them severe (ICANS 3-4). Two patients died at PICU (8.3%) because of refractory CRS-hemophagocytic lymphohistyocitosis (carHLH) syndrome. There were no significant differences in relapse rate after CAR-T in patients requiring PICU, it was more frequently CD19 negative (p=0.344). PICU admission after CAR-T therapy was mainly due to CRS. Supportive treatment allowed effective management and high survival. Some patients presenting with carHLH, can suffer a fulminant course.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103).Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission. What is Known:• Acute leukaemia is the most common childhood cancer. Admission to a paediatric intensive care unit is required in 30% of children with acute leukaemia.• Regarding the outcomes of children with acute leukaemia that require admission to the intensive care unit data are scarce.What is New:• Mortality in acute leukaemia patients admitted to the paediatric intensive care unit is lower than that of patients with a history of stem cell therapy but higher than that of patients with solid tumours.• The main reason for admission was sepsis, which is related in literature to more severity and long length of stay.

The presence of mutations in PRF1, UNC13D, STX11 and STXBP2 genes in homozygosis or compound heterozygosis results in immune deregulation. Most such cases lead to clinical manifestations of haemophagocytic lymphohistiocytosis (HLH). In the present study, we analyzed degranulation and cytotoxicity in a pediatric patient with a late presentation of HLH associated with Epstein–Barr virus infection. Remarkably, the results of the degranulation assay showed reduction of CD107a median fluorescence intensity (MFI) and absent cytotoxicity. Genetic analysis identified compound heterozygous mutations in STXBP2 gene: a previously reported splicing defect in exon 15 (c.1247-1G>C, p.V417LfsX126) and a novel missense mutation in exon 9 (c.728T>G, p.L243R). Transfection experiments of STXBP2-L243R or STXBP2-WT constructs showed an undetectable protein expression of the STXBP2-L243R mutation. The residue L243 is highly preserved evolutionarily; moreover, computational analysis of its structure revealed its participation in the rich network of interactions that stabilizes domains 2 and 3 of the protein. Altogether, we demonstrated by molecular and in silico analysis that the new L243R mutation in STXBP2 plays a pathogenic role that, together with the p.Val417Leufsc mutation, shows the synergistic negative effect of these two mutations on STXBP2 function, leading to a decrease of degranulatory activity in vivo.

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myelodysplastic/myeloproliferative neoplasm characterized by distinct epigenetic signatures that facilitate molecular classification. This study aimed to evaluate the diagnostic utility of locus-specific DNA methylation in the bone morphogenetic protein 4 ( BMP4 ) gene as a single predictor of disease outcomes in a cohort of 111 children diagnosed with JMML, alongside 9 healthy controls. Methylation levels of BMP4 , assessed through targeted bisulfite next-generation sequencing (bs-NGS), were heterogeneous within the JMML cohort and were significantly associated with clinical risk factors, such as patient age, and fetal hemoglobin (HbF) levels. A comparative analysis of BMP4 bs-NGS and genome-wide methylation array data revealed a strong positive correlation ( p  < 0.001). The sensitivity and specificity of BMP4 bs-NGS for classifying high-methylation cases were 0.612 and 0.887, respectively. For PTPN11 -mutant patients ( N  = 40), the sensitivity was 0.667 and the specificity was 0.842. Survival analysis indicated that patients with high BMP4 methylation ( BMP4 h) had lower 5-year disease-free survival (DFS) rates than those with normal BMP4 methylation ( BMP4 n). Specifically, the 20% of patients with highest BMP4 methylation had a 5-year DFS of 0.38, in contrast to 0.62 for the lowest 20% ( p  = 0.007). These findings highlight the potential of BMP4 methylation analysis as a complementary biomarker for JMML risk stratification, mirroring genome-wide methylation profiles known to associate with prognostic subgroups.

GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p  = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.

The Mediterranean region and the Levant have returned some of the clearest evidence of a climatically dry period occurring around 4200 years ago. However, some regional evidence is controversial and contradictory, and issues remain regarding timing, progression, and regional articulation of this event. In this paper, we review the evidence from selected proxies (sea-surface temperature, precipitation, and temperature reconstructed from pollen, δ18O on speleothems, and δ18O on lacustrine carbonate) over the Mediterranean Basin to infer possible regional climate patterns during the interval between 4.3 and 3.8 ka. The values and limitations of these proxies are discussed, and their potential for furnishing information on seasonality is also explored. Despite the chronological uncertainties, which are the main limitations for disentangling details of the climatic conditions, the data suggest that winter over the Mediterranean involved drier conditions, in addition to already dry summers. However, some exceptions to this prevail – where wetter conditions seem to have persisted – suggesting regional heterogeneity in climate patterns. Temperature data, even if sparse, also suggest a cooling anomaly, even if this is not uniform. The most common paradigm to interpret the precipitation regime in the Mediterranean – a North Atlantic Oscillation-like pattern – is not completely satisfactory to interpret the selected data.