bims-conane 2026-01-18 papers

Stem Cell Res. 2026 Jan 07. pii: S1873-5061(26)00004-8. [Epub ahead of print]91 103908

Generation of iPSC and isogenic gene-corrected lines from a patient with RPS7 (c.277_279delGTC)-mutated Diamond-Blackfan anemia syndrome.

Shruthi Suryaprakash, Yan Ju, James P Papizan, Shondra M Pruett-Miller, Marcin W Wlodarski, Mitchell J Weiss, Lei Han, Senthil Velan Bhoopalan.

Diamond-Blackfan anemia syndrome (DBAS) is a heterogeneous genetic bone marrow failure disorder characterized by erythroid hypoplasia in young children. Most forms of DBAS are caused by heterozygous loss-of-function mutations in one of the 24 different ribosomal protein genes. We generated an iPSC line from a patient with a heterozygous RPS7 (c.277_279delGTC) mutation, along with a corresponding isogenic cell line wherein the mutation was corrected using Cas9-mediated homology-directed repair.

DOI: https://doi.org/10.1016/j.scr.2026.103908

Nucleic Acids Res. 2026 Jan 05. pii: gkaf1506. [Epub ahead of print]54(1):

HLTF cooperates with GATA1 to activate transcriptional programs and chromatin remodeling during erythroid development.

Han Gong, Bin Hu, Ling Nie, Huifang Zhang, Pan Wang, Wenwen Xu, Maohua Li, Li Liu, Ji Zhang, Xiaojuan Xiao, Long Liang, Yongbin Chen, Mao Ye, Narla Mohandas, Hongling Peng, Xu Han, Yue Sheng, Jing Liu.

Erythropoiesis, the process by which hematopoietic stem cells differentiate into mature red blood cells, is tightly regulated by a complex network of transcriptional and epigenetic mechanisms. While helicase-like transcription factor (HLTF) is known for its roles in transcriptional regulation, chromatin remodeling, and genome stability, its function in erythroid development has remained unexplored. Here, we identify HLTF as a novel regulator of GATA1 and erythropoiesis. HLTF directly binds the GATA1 promoter, enhancing its transcription. In vitro and in vivo assays demonstrated that HLTF promotes erythroid proliferation, survival, and terminal differentiation. HLTF knockout impairs erythropoiesis, effects which are partially rescued by GATA1 overexpression. Multi-omics analyses (RNA-seq, ATAC-seq, and CUT&Tag) reveal that HLTF maintains chromatin accessibility and activates erythroid gene networks. HLTF interacts with GATA1, co-occupies erythroid regulatory regions, and facilitates GATA1 genomic binding. Notably, GATA1 also transcriptionally activates HLTF, forming a positive feedback loop. In erythroid disorders, HLTF is up-regulated in polycythemia vera (PV) and down-regulated in myelodysplastic syndromes (MDS). 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.

DOI: https://doi.org/10.1093/nar/gkaf1506

Blood. 2026 Jan 12. pii: blood.2025029196. [Epub ahead of print]

Long-term efficacy and safety results of betibeglogene autotemcel gene therapy for transfusion-dependent β-thalassemia.

Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia (TDT) involves autologous transplantation of hematopoietic stem and progenitor cells transduced with a modified β-globin gene to produce functional adult hemoglobin (HbAT87Q). Sixty-three participants with TDT (median [range] age: 17 [4-35] years) received beti-cel in phase 1/2 (n = 22) or phase 3 (n = 41) studies and enrolled in the long-term follow-up LTF-303 study (clinicaltrials.gov/NCT02633943; median [range] follow-up: 5.9 [2.9-10.1] years). Manufacturing refinements in phase 3 increased transduction efficiency, resulting in higher drug product vector copy number and HbAT87Q levels, which translated into higher hemoglobin and transfusion independence (TI) rates compared with phase 1/2. TI was achieved by 68.2% (15/22) of phase 1/2 participants (median weighted average Hb during TI, 10.2 g/dL) and 90.2% (37/41) of phase 3 participants (median, 11.2 g/dL) and was sustained through last follow-up. Treatment efficacy was similar across ages and TDT genotypes. Among participants achieving TI, 73% (38/52) had discontinued iron chelation at last follow-up, with no increase in liver iron concentration. Markers of ineffective erythropoiesis, including serum transferrin receptor and erythropoietin, improved with restoration of iron homeostasis. Health-related quality-of-life assessment scores showed durable improvements. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. These findings establish beti-cel as a durable, one-time therapy that achieves TI, restores iron balance, and improves quality of life, offering a potentially curative treatment option for people with TDT.

DOI: https://doi.org/10.1182/blood.2025029196

Blood. 2026 Jan 12. pii: blood.2025030137. [Epub ahead of print]

Optimized CRISPR-Cas12a genome-wide screen reveals PTPA phosphatase pathway in fetal hemoglobin silencing.

Elizabeth A Traxler, Quynn Hotan, Yue Shao, Chad Komar, Qingzhou Chen, Megan S Saari, A Josephine Thrasher, Shuchen Yang, Kunhua Qin, Michelle Wang, Scott A Peslak, Osheiza Abdulmalik, Belinda M Giardine, Cheryl A Keller, Ross C Hardison, Andy J Minn, Eugene Khandros, Junwei Shi, Gerd A Blobel.

Reactivating the fetal globin genes HBG1 and HBG2 in adult erythroid cells represents a validated therapeutic approach for hemoglobinopathies. Central mediators of the fetal-to-adult hemoglobin transition include the direct transcriptional HBG1/2 repressors BCL11A1,2, LRF3, and NFIA/X4. Limited-scale screens have attempted to expand the regulatory circuity surrounding fetal globin silencing, but systematic genome-wide dissection of such pathways is lacking. We employed a two-tiered genetic screening strategy - a novel CRISPR-Cas12a-based screening platform followed by a domain-focused CRISPR-Cas9 screen - to interrogate all known human coding genes for their impact on HBG1/2 regulation and erythroid cellular fitness, generating a comprehensive resource for the field. Among the top hits was PTPA, an activator of the serine-threonine phosphatase PP2A whose loss elevates HBG1/2 levels while preserving erythroid differentiation. Phenotypic rescue experiments revealed that PTPA silences HBG1/2 expression primarily by regulating BCL11A expression. To our knowledge, this study represents the most comprehensive CRISPR dissection of HBG regulation to date, highlighting the power of Cas12a-based genome-scale screening for uncovering disease-relevant pathways.

DOI: https://doi.org/10.1182/blood.2025030137