bims-conane 2026-05-31 papers

Hemoglobin. 2026 May 24. 1-9

Unstable Hemoglobin Variants: Molecular Mechanisms, Clinical Phenotypes, and a Practical Diagnostic and Management Approach.

Aikaterini Poulaki, Sophia Delicou.

Unstable hemoglobin variants are rare structural hemoglobin disorders in which alterations in the globin chain reduce hemoglobin stability, promoting denaturation, precipitation, and red cell injury. Affected individuals may present with a broad spectrum, ranging from compensated hemolysis to severe transfusion-dependent anemia, and episodes are commonly exacerbated by intercurrent illness or oxidative stress. Diagnosis remains challenging because many unstable variants are not readily recognized by routine hemoglobin separation, and classic morphological clues (Heinz bodies; bite/blister cells) are neither uniformly present nor specific. This review summarizes the molecular mechanisms underlying hemoglobin instability, outlines phenotypic patterns across the lifespan (including neonatal-limited instability involving fetal hemoglobin), and provides a practical diagnostic framework that integrates hemoglobin separation methods, stability assays, and molecular testing. Supportive care, including avoidance of oxidant triggers, folate supplementation, and transfusion support when needed, remains the mainstay, while splenectomy and curative transplantation are reserved for selected severe cases.

Keywords: Unstable hemoglobin; diagnosis; hemoglobinopathies; management

DOI: https://doi.org/10.1080/03630269.2026.2674946

Blood. 2026 May 29. pii: blood.2026033804. [Epub ahead of print]

Dissecting polycomb complexes for enhanced fetal hemoglobin production.

Paul Kaminski, Kristen Min, Elizabeth A Traxler, Eugene Khandros, Osheiza Abdulmalik, Bailey N Godfrey, Cheryl A Keller, Belinda M Giardine, Ross C Hardison, Junwei Shi, Gerd A Blobel.

Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and b-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) can be reactivated in adult erythroid cells by selective perturbations of PRC1 or PRC2 components without complete loss of PRC function. A high-density CRISPR-Cas9 mutagenesis screen identified a region in the EZH2 subunit where Cas9 induced exon 14 skipping (EZH2D14). EZH2D14, which lacks a portion of the CXC domain, relieves HbF repression while largely maintaining cellular fitness. EZH2D14 retains H3K27 methylation and repression of a PRC target gene subset. Experiments in cells derived from mice bearing human b-globin genes confirm that pathways mediating EZH2 control of HbF expression can function in a mouse model of HBG switching. These findings demonstrate that partial disruption of PRC can yield selective phenotypes, highlighting the therapeutic potential of targeting non-enzymatic domains within chromatin-modifying complexes.

DOI: https://doi.org/10.1182/blood.2026033804

Eur J Pharmacol. 2026 May 27. pii: S0014-2999(26)00522-4. [Epub ahead of print]1029 179040

Combination of Deferoxamine and Deferiprone demonstrates superior efficiency compared to monotherapies in management of cardiac iron overload: Evidence from meta-analysis.

Subhangi Basu, Swagatam Pal, Deblina Sarkar, Annesa Mukherjee, Neil Chakrabarti, Praphulla Chandra Shukla, Nishant Chakravorty.

OBJECTIVE: Cardiac iron overload is a significant but treatable complication linked to various diseases. Iron chelators, such as Deferasirox (DFX), Deferiprone (DFP), and Deferoxamine (DFO), are commonly prescribed either as monotherapy or in combination for the treatment of systemic iron overload. However, the management of cardiac iron overload remains challenging owing to the absence of a standardized chelation regimen exclusively for the management of the condition in patients. This meta-analysis intends to evaluate the comparative efficacy of different iron chelation regimens for the treatment of cardiac iron overload.
METHODS: The meta-analysis included twenty-nine studies (2000-2025) and applied a random-effects model to calculate Hedges' g summary effect and assess heterogeneity to assess the efficacy of the chelation regimens in increasing cardiac T2∗ values. Pooled analysis of cardiac T2∗ change between chelation regimens for patients with significant cardiac iron overload was also performed to establish the most effective chelation regimen for the treatment of this condition.
RESULTS: Among the iron chelation therapies, DFO-DFP combination produced the largest and significant improvement (Hedges' g = 1.11), followed by DFX-DFO combination (Hedges' g = 0.53). In patients with baseline cardiac T2∗ <20 ms, DFO-DFP combination achieved the greatest mean increase of cardiac T2∗ values (7.51 ms), followed by DFO monotherapy and DFX-DFO combination.
CONCLUSION: The combination of Deferoxamine and Deferiprone demonstrated comparatively greater efficacy than the other evaluated regimens in decreasing cardiac iron overload. However, this finding should be interpreted with caution in consideration of the study limitations when applied to clinical decision-making.

Keywords: Cardiac T2∗ MRI; Cardiac iron overload; Deferasirox; Deferiprone; Deferoxamine

DOI: https://doi.org/10.1016/j.ejphar.2026.179040

Blood Red Cells Iron. 2025 Sep;pii: 100010. [Epub ahead of print]1(2):

Restricting glycine uptake with bitopertin improves erythropoiesis in preclinical models of Diamond-Blackfan anemia.

Raymond T Doty, Adam D Munday, Hannah Cottnair, Sarah E Funk, David J Young, Cynthia E Dunbar, Min Wu, Janis L Abkowitz.

Diamond-Blackfan anemia (DBA) results from germ line haploinsufficiency of 1 of at least 26 distinct ribosomal proteins. Although patients with DBA have hematopoietic stem and progenitor cell defects, the dominant clinical phenotype is severe anemia. In ~60% of patients with DBA, the anemia responds to corticosteroids. However, these responses are often time limited, and steroid-related complications are common, leaving an unmet need for an effective and safe oral therapy. In DBA, ribosomal haploinsufficiency leads to slowed translation and impaired protein synthesis. Globin synthesis is significantly slowed, whereas the production of heme, which requires a small amount of protein because it is synthesized enzymatically, proceeds at a near normal rate. This results in an excess of intracellular heme in early erythroblasts, elevated reactive oxygen species, and other heme-induced toxicity. Bitopertin, an oral competitive inhibitor of glycine import, has been shown to reduce heme synthesis and to have an excellent safety profile in unrelated phase 2 and 3 studies. We reasoned that bitopertin might help balance heme synthesis with globin synthesis and improve erythropoiesis in patients with DBA. Our observations in samples from patients with DBA, CD34+ cells engineered to downregulate RPS19, and a murine DBA model support this concept, justify ongoing clinical studies, and provide insight into optimal trial design.

DOI: https://doi.org/10.1016/j.brci.2025.100010