[The mechanism of MLL-rearranged leukemogenesis and its targeted therapies].
Rinsho Ketsueki
; 62(8): 988-997, 2021.
Article
em Ja
| MEDLINE
| ID: mdl-34497239
ABSTRACT
Leukemia is caused by uncontrolled proliferation of immature hematopoietic progenitors. MLL fusion proteins, generated by chromosomal translocations, activate a broad range of previously transcribed genes to achieve the same expression profile as that of the parent cell in the daughter cells, thereby promoting self-renewal. Normally, replication of the expression profile only occurs in the hematopoietic stem cells (HSCs). A transactivation system comprised of MLL and AF4/ENL/P-TEFb (AEP) complexes promotes it by reactivating CpG-rich promoters. In the normal hematopoietic development, this system is tightly regulated and progressively suppressed during the course of hematopoietic differentiation so that non-HSC hematopoietic cells would not self-renew. Genetic mutations such as fusions of MLL and AEP components generate a constitutively active form of the MLL transcriptional machinery, which aberrantly promotes self-renewal even in non-HSC hematopoietic cells. In this review, I depict a molecular mechanism of MLL fusion-mediated leukemogenesis from a standpoint that leukemogenesis is driven by aberrant self-renewal that is mediated by hyper-active transcriptional machinery, and introduce several molecularly targeted therapies in the making which specifically perturb this transactivation system.
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Base de dados:
MEDLINE
Assunto principal:
Leucemia
/
Proteína de Leucina Linfoide-Mieloide
Limite:
Humans
Idioma:
Ja
Ano de publicação:
2021
Tipo de documento:
Article