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Simple Summary: A predisposition to myeloid neoplasms has recently been recognized as a defined clinical entity by the World Health Organization. One of the most well-known syndromes within this group is GATA2 deficiency, which is a highly heterogeneous disorder that can include pulmonary and vascular involvement, immunodeficiency, and myeloid neoplasms. The only curative treatment for this syndrome is allogeneic hematopoietic stem cell transplantation (HSCT), which should be performed in patients with GATA2 deficiency before irreversible organ damage. These patients should be referred to a multidisciplinary team to assess all potential and specific organ-system manifestations that could impact the patient's treatment, and consultations with appropriate subspecialists should be facilitated. Additionally, genetic testing should be offered to first-degree relatives, particularly those considered for donation when an HSCT with a sibling donor is feasible. Hereditary myeloid malignancy syndromes (HMMSs) are rare but are becoming increasingly significant in clinical practice. One of the most well-known syndromes within this group is GATA2 deficiency. The GATA2 gene encodes a zinc finger transcription factor essential for normal hematopoiesis. Insufficient expression and function of this gene as a result of germinal mutations underlie distinct clinical presentations, including childhood myelodysplastic syndrome and acute myeloid leukemia, in which the acquisition of additional molecular somatic abnormalities can lead to variable outcomes. The only curative treatment for this syndrome is allogeneic hematopoietic stem cell transplantation, which should be performed before irreversible organ damage happens. In this review, we will examine the structural characteristics of the GATA2 gene, its physiological and pathological functions, how GATA2 genetic mutations contribute to myeloid neoplasms, and other potential clinical manifestations. Finally, we will provide an overview of current therapeutic options, including recent transplantation strategies. [ABSTRACT FROM AUTHOR]

The molecular landscape of acute lymphoblastic leukemia (ALL) is highly heterogeneous, and genetic lesions are clinically relevant for diagnosis, risk stratification, and treatment guidance. Next-generation sequencing (NGS) has become an essential tool for clinical laboratories, where disease-targeted panels are able to capture the most relevant alterations in a cost-effective and fast way. However, comprehensive ALL panels assessing all relevant alterations are scarce. Here, we design and validate an NGS panel including single-nucleotide variants (SNVs), insertion–deletions (indels), copy number variations (CNVs), fusions, and gene expression (ALLseq). ALLseq sequencing metrics were acceptable for clinical use and showed 100% sensitivity and specificity for virtually all types of alterations. The limit of detection was established at a 2% variant allele frequency for SNVs and indels, and at a 0.5 copy number ratio for CNVs. Overall, ALLseq is able to provide clinically relevant information to more than 83% of pediatric patients, making it an attractive tool for the molecular characterization of ALL in clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: TWEAK is an inflammatory cytokine related to prostate cancer (PCa) progression that exerts its effects by engaging its cognate receptor Fn14. A soluble form of TWEAK (sTWEAK) has been detected in the PCa microenvironment. Altered levels of circulating sTWEAK are associated with aberrant glucose metabolism. We show that reduced serum levels of sTWEAK are associated with the metabolic status in patients with PCa and that the treatment of PC-3 cells with sTWEAK enhances the expression of genes related to lipid, but not to glucose, metabolism. sTWEAK also increases the lipid uptake and lipid accumulation in PC-3 cells. We corroborated that the observed effects were due to TWEAK/Fn14 engagement by silencing Fn14 expression, which attenuated the aberrant gene and protein expression. Additionally, we observed that the phosphorylation of ERK1/2 and AKT (ser473) were required for TWEAK/Fn14 actions. Thus, the contribution of the sTWEAK/Fn14 axis on PCa metabolism supports its potential as a therapeutic target for PCa. Soluble TWEAK (sTWEAK) has been proposed as a prognostic biomarker of prostate cancer (PCa). We found that reduced serum levels of sTWEAK, together with higher levels of prostate-specific antigen and a higher HOMA-IR index, are independent predictors of PCa. We also showed that sTWEAK stimulus failed to alter the expression of glucose transporter genes (SLC2A4 and SLC2A1), but significantly reduced the expression of glucose metabolism-related genes (PFK, HK1 and PDK4) in PCa cells. The sTWEAK stimulation of PC-3 cells significantly increased the expression of the genes related to lipogenesis (ACACA and FASN), lipolysis (CPT1A and PNPLA2), lipid transport (FABP4 and CD36) and lipid regulation (SREBP-1 and PPARG) and increased the lipid uptake. Silencing the TWEAK receptor (Fn14) in PC-3 cells confirmed the observed lipid metabolic effects, as shown by the downregulation of ACACA, FASN, CPT1A, PNPLA2, FABP4, CD36, SREBP-1 and PPARG expression, which was paralleled by a reduction of FASN, CPT1A and FABP4 protein expression. Specific-signaling inhibitor assays show that ERK1/2 and AKT (ser473) phosphorylation can regulate lipid metabolism-related genes in PCa cells, pointing to the AKT locus as a possible target for PCa. Overall, our data support sTWEAK/Fn14 axis as a potential therapeutic target for PCa. [ABSTRACT FROM AUTHOR]