Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.
Exp Hematol Oncol
; 12(1): 81, 2023 Sep 22.
Article
em En
| MEDLINE
| ID: mdl-37740239
ABSTRACT
In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2AAFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2AAFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/CD133, while other KMT2AAFF1 target genes, including HOXA9 and CDK6 remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Exp Hematol Oncol
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Holanda