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Introduced by Associate Editor Catherine Bollard, this review series focuses on the state of the art of gene therapy for sickle cell disease and hemophilia. These papers review the range of clinical trials for gene therapy of these two inherited diseases, with a focus on outcomes and safety. In addition, we include a Perspective article reflecting on the development of hematologic malignancy in 2 patients after gene therapy for sickle cell disease, which led to a brief suspension of 1 clinical trial that has now resumed enrollment.





Paietta and colleagues performed extensive genomic analysis of a cohort of over 200 adults with BCR-ABL-negative B-cell acute lymphoblastic leukemia (B-ALL) treated in a large clinical trial. Adding gene expression profiling, immunophenotypic analysis, and fusion polymerase chain reaction predicted survival better than traditional stratification by age and white blood cell count, mainly by allowing reassignment of high risk patients to standard or immediate risk groups based on genomic analysis.

The serum and glucocorticoid-regulated kinase 1 gene (SGK1), one of the most commonly mutated genes in diffuse large B-cell lymphoma (DLBCL), has been widely assumed to be a tumor suppressor that is inactivated by loss-of-function mutations. Gao et al challenge this paradigm, demonstrating that N-terminal truncation mutations remove the degradation domain, leading to truncated hyperstable proteins that retain kinase activity, thereby enhancing proliferation and resistance to AKT inhibition. This suggests SGK1 inhibition as a potential target for therapy of DLBCL.


Clonal cytopenia of undetermined significance (CCUS) is associated with increased risk of myeloid neoplasm (MN); however, predicting risk of evolution to MN is difficult. In this month’s CME article, Gallì et al describe clonal dynamics in a large cohort of patients with (1) idiopathic cytopenia of undetermined significance (ICUS), (2) no hematologic abnormalities, (3) unexplained anemia, and (4) overt MN. Thirty percent of patients with ICUS could be reassigned as having CCUS. The authors further report that the nature of the clonal mutations, the combination of different mutations, and the variant allele fractions allow patients to be separated into groups with divergent likelihood of developing MN.


Neutrophil extracellular traps (NETs) are important in the response to infection but can also mediate excessive inflammation. Neonatal neutrophils do not form NETs because of circulating NET-inhibitory peptides (NIPs). Campbell and colleagues report that α1-antitrypsin (A1AT) is cleaved by high-temperature requirement serine protease A1 (HTRA1) to form NIPs. HTRA1-null mice become NET competent, and administration of the A1AT cleavage fragment improves survival in a neonatal sepsis model, confirming that HTRA1 cleaves A1AT to modulate NET formation.


Komrokji et al examined the proposed international working group proposal to designate SF3B1-mutant myelodysplastic syndrome (MDS) as a unique disease entity, using a single-institution validation cohort of 1779 MDS patients, of whom 320 harbored SF3B1 mutations. They confirmed the demographics of older age, low-risk disease, ring sideroblasts, and low blast percentage. They further confirmed better overall survival that is negatively impacted in those patients with concomitant mutations, high variant allele fraction, and increased blast percentage.



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