Portal de investigación
A heterozygous CEBPA mutation disrupting the bZIP domain in a RUNX1 and SRSF2 mutational background causes MDS disease progression
Fecha de publicación:
Fecha Ahead of Print:
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Almaghrabi, R
- Alyahyawi, Y
- Keane, P
- Mian, SA
- Habel, K
- Atkinson, A
- Ward, C
- Bayley, R
- Menendez, P
- Murphy, GJ
- Sobahy, T
- Baghdadi, MA
- Flemban, AF
- Kabrah, SM
- Torres-Ruiz, R
- Papapetrou, EP
- Akerman, I
- Raghavan, M
- Bonnet, D
- Bonifer, C
- Garcia, P
Grupos
Abstract
Myelodysplastic syndrome disease (MDS) is caused by the successive acquisition of mutations and thus displays a variable risk for progression to AML. Mutations in CEBPA are commonly associated with a high risk of disease progression, but whether they are causative for AML development is unclear. To analyse the molecular basis of disease progression we generated MDS patient-derived induced pluripotent stem cells from a low risk male patient harbouring RUNX1/SRSF2 mutations. This experimental model faithfully recapitulates the patient disease phenotypes upon hematopoietic differentiation. Introduction of a frameshift mutation affecting the C/EBP alpha bZIP domain in cells from low-risk stages mimicks disease progression by reducing clonogenicity of myeloid cells, blocking granulopoiesis and increasing erythroid progenitor self-renewal capacity. The acquisition of this mutation reshapes the chromatin landscape at distal cis-regulatory regions and promotes changes in cellular composition as observed by single cell RNAseq. Mutant C/EBP alpha is therefore causative for MDS disease progression. Our work identifies mutant CEBPA as causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies.
© 2025. The Author(s).
Datos de la publicación
- ISSN/ISSNe:
- 2041-1723, 2041-1723
- Tipo:
- Article
- Páginas:
- 5489-5489
- PubMed:
- 40593493
- Factor de Impacto:
- 4,846 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
Nature Communications NATURE PORTFOLIO
Citas Recibidas en Web of Science: 3
Documentos
Filiaciones
Proyectos y Estudios Clínicos
Emerging biomarkers and targeted therapies in acute myeloid leukemia. combining omics data with machine learning. (nuevos biomarcadores y terapias dirigidas en la leucemia mieloide aguda. combinación de datos ómicos con machine learning).
Investigador Principal: EVA BARRAGÁN GONZÁLEZ
PI19/00730 . INSTITUTO DE SALUD CARLOS III . 2020
Cita
Almaghrabi R,Alyahyawi Y,Keane P,Mian SA,Habel K,Atkinson A,Ward C,Bayley R,SARGAS C,Menendez P,Murphy GJ,Sobahy T,Baghdadi MA,Flemban AF,Kabrah SM,Torres R,Papapetrou EP,Akerman I,Raghavan M,BARRAGAN E,Bonnet D,Bonifer C,Garcia P. A heterozygous CEBPA mutation disrupting the bZIP domain in a RUNX1 and SRSF2 mutational background causes MDS disease progression. Nat. Commun. 2025. 16. (1):p. 5489-5489. IF:18,100. (1).