TIF1ß activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia.
Leukemia
; 38(6): 1275-1286, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38734786
ABSTRACT
TIF1ß/KAP1/TRIM28, a chromatin modulator, both represses and activates the transcription of genes in normal and malignant cells. Analyses of datasets on leukemia patients revealed that the expression level of TIF1ß was increased in patients with chronic myeloid leukemia at the blast crisis and acute myeloid leukemia. We generated a BCRABL1 conditional knock-in (KI) mouse model, which developed aggressive myeloid leukemia, and demonstrated that the deletion of the Tif1ß gene inhibited the progression of myeloid leukemia and showed longer survival than that in BCRABL1 KI mice, suggesting that Tif1ß drove the progression of BCRABL1-induced leukemia. In addition, the deletion of Tif1ß sensitized BCRABL1 KI leukemic cells to dasatinib. The deletion of Tif1ß decreased the expression levels of TIF1ß-target genes and chromatin accessibility peaks enriched with the Fosl1-binding motif in BCRABL1 KI stem cells. TIF1ß directly bound to the promoters of proliferation genes, such as FOSL1, in human BCRABL1 cells, in which TIF1ß and FOSL1 bound to adjacent regions of chromatin. Since the expression of Fosl1 was critical for the enhanced growth of BCRABL1 KI cells, Tif1ß and Fosl1 interacted to activate the leukemic transcriptional program in and cellular function of BCRABL1 KI stem cells and drove the progression of myeloid leukemia.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Proteínas de Fusão bcr-abl
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article