Molecular pathology selected abstracts

Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, molecular pathologist, Sonic Healthcare USA, Rye Brook, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.

Impact of evolution of Mycobacterium tuberculosis transcription regulation

December 2025—Compared with many other pathogens, Mycobacterium tuberculosis is highly genomically conserved—it does not engage in horizontal gene transfer and it has a lower mutation rate. However, experimental and epidemiologic studies suggest that Mycobacterium tuberculosis (Mtb) strains differ with regard to disease manifestation, rates of relapse, and transmissibility. The authors recently developed new RNA sequencing and phylogenomic tools to study hundreds of Mtb isolate transcriptomes, assessing links between transcriptional and genetic variation as well as between variants and epidemiologic traits. They discovered diversity in virulence gene expression across 274 Mtb clinical isolates, many of which harbored variants associated with decreased expression of EsxA (ESAT-6) and EsxB (CFP-10), which are virulence effectors, dominant T-cell antigens, and immunodiagnostic targets. Variants in the regulator whiB6 were linked with downregulation of essential ESX-1-secreted virulence factors. A temporal analysis showed that in Mtb lineages in which selection of whiB6 variants was strongest, these variants emerged relatively recently and were associated with high-level drug resistance and increased transmission of drug-resistant strains. The authors also identified the emergence of whiB6 variants as a relatively ancient event in lineage one, suggesting that modern drug pressure alone may not explain the emergence of these variants. In addition to the possibility that these whiB6 variants may contribute to drug resistance, the authors proposed that the variants, by favoring less severe or asymptomatic disease, may allow variant strains to avoid detection and treatment, enabling more aggregate transmission over time. However, the authors noted that the drug-sensitive isolates used for transcriptional analyses in this study were limited to communities in Vietnam and Peru and that these isolates did not represent the genetic diversity of Mtb. While the study has some limitations, it provides additional insight into the evolution of Mtb, particularly with regard to drug resistance and virulence. The data also have implications for Mtb diagnostics and vaccine development given that some of the ESX-1 effectors that were identified are antigens involved in Mtb diagnostic assays or targets for vaccine design, or both.

Culviner PH, Frey AM, Liu Q, et al. Evolution of Mycobacterium tuberculosis transcription regulation is associated with increased transmission and drug resistance. Cell. 2025. doi.org/10.1016/j.cell.2025.09.005

Correspondence: Dr. Sarah M. Fortune at [email protected]

Significance of preleukemic somatic GATA1 mutations in children with Down syndrome

Children with constitutional trisomy 12 and Down syndrome have a high risk of developing myeloid leukemia associated with Down syndrome before four years of age. The disease does not occur in children who do not have trisomy 21. Transient abnormal myelopoiesis (TAM), which precedes myeloid leukemia associated with Down syndrome (ML-DS), is a clonal process that can be silent or clinically overt. Both TAM and ML-DS are defined in part by the presence of one or more somatic mutations in the GATA1 gene. These mutations, which result in the production of a shorter N-terminally truncated GATA1 protein (GATA1s), are considered necessary, though not sufficient alone, for the development of ML-DS and are thought to arise in utero. However, data on the significance of GATA1 mutations for individual babies and whether GATA1s mutations can occur after birth are limited. Therefore, the authors conducted a study to explore these areas. They performed next-generation sequencing (NGS)-based GATA1 mutation analysis and hematologic and clinical evaluation during the four-year window of ML-DS risk for a cohort of 450 neonates with Down syndrome. Screening with NGS identified GATA1s mutations in 25 percent of the neonates studied. Among that group, 48 percent had peripheral blood blasts of 10 percent or more and were designated clinical TAM, and 52 percent had fewer than 10 percent blasts and were designated silent TAM. The variant allele frequency of the GATA1s mutations, which varied from 0.3 to 89 percent, positively correlated with percent blasts, white blood cell count, dyserythropoiesis, dysmegakaryoypoiesis, and clinical disease severity. One of 54 (1.9 percent) babies with TAM died as a result of the disease. Of 110 surviving neonates with GATA1s mutations at birth, seven (6.4 percent) developed ML-DS, all before age two years (median age, 17.5 months). GATA1s clone size and blast percentage at birth were the only predictors of ML-DS, though only blast percentage at birth remained significant on multivariate analysis using Cox multiple regression analysis. All study patients with GATA1s mutations detectable at six months of age or older developed ML-DS. Persistence of blasts or reappearance of blasts at low levels and decreasing platelet count appeared to be the best predictors of impending transformation to ML-DS. No neonates lacking GATA1s mutations at birth acquired the mutations after birth or developed ML-DS. This study provides additional data regarding the natural history and clinical significance of GATA1s mutations in neonates with Down syndrome. In addition to allowing more accurate counseling of parents who have children with Down syndrome, this information could assist in developing evidence-based guidelines regarding Down syndrome risk and monitoring for TAM and ML-DS.

Elliott N, Bhatnagar N, Buck G, et al. Clinical significance of preleukemic somatic GATA1 mutations in children with Down syndrome. Blood. 2025;146(13):1561–1574.

Correspondence: Dr. Irene Roberts at [email protected] or Dr. Paresh Vyas at [email protected]