Functional assessment of inherited myeloid neoplasm-associated SAMD9L germline variants via Monoallelic CRISPR modelling.

Autores de IIS La Fe

• Elena Vuelta Ramos

  Autor

• Alessandro Liquori

  Autor

• Marta Santiago Balsera

  Autor

• José Vicente Cervera Zamora

  Autor

• Alejandra Sanjuan Pla

  Autor

Participantes ajenos a IIS La Fe

• Morín M
• Soletto L
• Marugal MÁ
• Gallardo M
• Moreno-Pelayo MÁ

Grupos

• Hematología y Hemoterapia

Abstract

While the majority of myeloid neoplasms are sporadic, the increasing application of germline genetic testing has led the World Health Organization to designate 'Myeloid malignancies with germline predisposition' as a distinct clinical entity, carrying major implications for clinical care and research. Germline variants in the Sterile alpha motif domain-containing 9-like (SAMD9L) gene are specifically associated with an increased risk for these malignancies. In this study, we functionally modelled two novel SAMD9L variants-p.N697Y and p.K1294*-alongside two previously reported variants (p.T233N and p.H880Q). We generated heterozygous knock-in cellular models in the Human leukemia (HL-60 myeloid cell line) for each variant using homology-directed repair-based Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Functional assays, focused on proliferation and protein translation, confirmed that the p.T233N, p.N697Y and p.K1294* variants all caused a decreased rate of protein translation. These results provide functional evidence to fine-tune the classification of these SAMD9L variants and significantly advance our understanding of the molecular mechanisms by which SAMD9L variants drive inherited myeloid neoplasms.

© 2026 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Keywords

• CRISPR/Cas9 gene editing; SAMD9L; inherited myeloid neoplasms