GATA1 (GATA Binding Protein 1)

Mechanistically, loss of LLPS reduced GATA1 chromatin occupancy, impaired its assembly with cofactors such as FOG1 and LMO2, and abrogated activation of erythroid gene promoters in luciferase assays, leading to defective terminal differentiation. Together, these findings uncover a previously unrecognized mechanism by which GATA1 regulates erythropoiesis through LLPS and highlight modulation of its IDR2 domain and post-translational modifications as potential therapeutic strategies for erythroid-related disorders.

Consequently, ectopic expression of BCL11A in LDB1-deficient proerythroblasts promotes their proliferation by rescuing them from ROS-mediated apoptosis. These findings highlight the essential role of LDB1 in fetal globin silencing during erythropoiesis.

LSPC-Cycle, FLT3-ITD and NUP98::KDM5A were considered independent prognostic factors in multivariate analysis. Findings indicate the prognostic relevance of cellular hierarchy and the importance of integrating hierarchy-specific molecular profiles for improved risk stratification and treatment formulation.

Importantly, PKM expression is also significantly elevated in DBA patients with RPS19 mutations, which is associated with reduced levels of GATA1, further supporting a link between GATA1s-driven defective erythropoiesis and dysregulated glycolysis. Together, these findings reveal that GATA1 controls not only heme metabolism, but also glycolytic reprogramming.

Advances in therapy now directly target these mechanisms: Luspatercept, a TGF-β ligand trap, has transformed care in β-thalassemia and MDS by restoring late-stage differentiation, while anti-inflammatory strategies, metabolic modulators, and gene editing approaches are being actively explored. Together, these discoveries reframe IE as a modifiable process rather than an inevitable consequence of disease. By distinguishing defective from IE and mapping their mechanistic underpinnings, this review outlines how novel therapeutic strategies can improve anemia, reduce systemic complications, and ultimately enhance outcomes in patients with erythroid disorders.

Knockout of HLTF in PV patient-derived cells suppressed erythroid hyperplasia, reduced chromatin accessibility, and impaired GATA1 binding. Together, these findings reveal HLTF as a transcriptional regulator of GATA1 and a pivotal modulator of erythropoiesis, providing new insights into erythroid lineage control and erythroid-related diseases.

However, p53 loss fails to normalize replication stress, allowing for the accumulation of DNA damage over time which increases the likelihood for leukemic transformation. Our data uncover the pathogenesis of ERCC6L2 disease and provide a prototypic example of clonal compensation in BMF syndromes, where somatic mutations in leukemia-associated genes - in this case TP53 - transiently improve blood cell production at, however, the expense of increasing leukemogenic potential.

We outline the approach to diagnosis and management of these conditions during the neonatal period and their significance for the health of these children in the short and long term. Lastly, we review the nonmalignant hematological abnormalities seen in neonates with DS, which are due to the effects of the extra 21 chromosome in the absence of GATA1 mutations.

Overall, these findings suggest that MEG-01-derived EVs approximate certain aspects of megakaryocyte-lineage exosomes and activated platelet-like states, although they do not fully replicate native platelet biology. Notably, plasma exosomes show strong proteomic convergence with MEG-01 exosomes, whereas platelet exosomes retain distinct activation-related features.

Thus, targeting the GATA1/MTDH axis may present a promising therapeutic strategy for attenuating oxidative stress-induced damage in podocytes during CKD. KEY MESSAGES: Advanced Oxidative Protein Products (AOPPs) promote the accumulation of oxidative stress in circulation Metadherin is elevated in kidneys of AOPP-induced oxidative stress CKD model mice GATA1 controls transcription of MTDH in renal podocyte of CKD Silencing GATA1/MTDH axis interrupts β-catenin signaling and ameliorates podocyte injury and CKD pathology.

Roxadustat induces erythropoiesis in erythroleukemia primarily by targeting HIF-2α and was partially GATA1-dependent. Besides upregulating erythropoietin, our study revealed the HIF-α/GATA1 axis as another critical regulatory mechanism for hypoxia-driven erythropoiesis.

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