Improved risk assessment in adult BCR-ABL1-negative B-ALL, value of clone metrics in clonal cytopenias, a placental protease generates a peptide to inhibit NET formation
In this week’s episode, we will review an integrated analysis of one of the largest adult BCR-ABL1 negative B-ALL patient cohorts treated in a single trial, learn more about the genotypic and phenotypic features of patients with clonal cytopenias, and look at a study showing that a serine protease expressed in the placenta cleaves α1-antitrypsin to generate a fragment that inhibits formation of neutrophil extracellular traps in neonates.
Gene therapy for sickle cell disease: moving from the bench to the bedside
Gene therapy as a potential cure for sickle cell disease (SCD) has long been pursued given that this hemoglobin disorder results from a single point mutation. Advances in genomic sequencing, increased understanding of hemoglobin regulation and discoveries of molecular tools for genome modification of hematopoietic stem cells have made gene therapy for SCD possible. Gene addition strategies using gene transfer vectors have been optimized over the last few decades to enable expression of normal or anti-sickling globins as strategies to ameliorate SCD.
Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL
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.
SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence
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.
Relationship between clone metrics and clinical outcome in clonal cytopenia
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.
Placental HTRA1 cleaves α1-antitrypsin to generate a NET-inhibitory peptide
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.
