Genome Transcriptome Analysis Reveals More About Hairy Cell Leukemia

A whole-genome transcriptome sequencing (WGTS) study of hairy cell leukemia (HCL) has revealed a higher degree of genomic complexity than was previously known.

WGTS was performed on samples from 59 patients with HCL and revealed novel diverse coding and non-coding changes involving intracellular pathway regulators (DUSP6, PTPN6, and TMEM229A), cytoskeletal proteins (ACTB and MTSS1) and recurrent genomic abnormalities affecting genes involved in telomere maintenance (TERT and POT1).

Piers Blombery, MBBS, of Torsten Haferlach Leukaemiediagnostik Stiftung in Munich, Germany, and colleagues shared these findings at the 2022 American Society of Hematology Annual Meeting.

According to the abstract, HCL is commonly characterized by the BRAF V600E mutation. However, “targeted genomic approaches to date have not covered the full spectrum of genomic and transcriptomic abnormalities that may be present in HCL.”

Therefore, Blombery and colleagues wanted to create a more comprehensive knowledge of genomic abnormalities associated with HCL.

All samples had BRAF V600E mutations. Co-mutations were detected in KLF2 in 8% of samples, CDKN1B in 8% of samples, KMT2C in 5% of samples, and ARID1A in 5% of samples. Blombery and colleagues also detected several novel co-mutated genes: the JAK/STAT regulator PTPN6 (7%), MAPK pathway regulator DUSP6 (5%), SGK1 (5%), and ACTB (5%).

About one-third (32%) of patient samples also had copy number abnormalities. The most frequent of these was loss of 7q. POT1 gene expression was significantly lower in patients with 7q deletion compared with those without (P<.05).

Additionally, about one-third (27%) of patients had genomic abnormalities affecting genes involved in telomere biology, including TERT promoter mutations, TERT SVs, and deletions involving POT1.

Finally, the researchers assessed non-coding variants by performing an enrichment analysis using bipartite graph models. They found a high frequency of activation-induced cytidine deaminase included promotor/enhancer hypermutation of highly expressed genes including RHOH, MTSS1, ZFP36L1, TMSB4X, and KLF2.

According to the abstract, “these findings provide multiple future directions to investigate the unique biology of HCL and related neoplasms, in particular the specific consequences of regulatory element hypermutation and the avoidance of oncogene-induced senescence through aberrant telomere regulation.”

Reference

Blombery P, Walter W, Hutter S, et al. Novel Non-Coding, Coding and Structural Variants in Hairy Cell Leukemia from Whole Genome Transcriptome Sequencing. Abstract #1540. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.