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Cell Rep ; 42(2): 112099, 2023 02 28.
Article in English | MEDLINE | ID: mdl-36763502

ABSTRACT

MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of MLL-r in these patients, congenital leukemia is very rare with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-expresses MLL-ENL and LIN28B, we investigate the impact of LIN28B on AML. LIN28B impedes the progression of MLL-r AML through compromised leukemia-initiating cell activity and suppression of MYB signaling. Mechanistically, LIN28B directly binds to MYBBP1A mRNA, resulting in elevated protein levels of this MYB co-repressor. Functionally, overexpression of MYBBP1A phenocopies the tumor-suppressor effects of LIN28B, while its perturbation omits it. Thereby, we propose that developmentally restricted expression of LIN28B provides a layer of protection against MYB-dependent AML.


Subject(s)
Leukemia, Myeloid, Acute , Myeloid-Lymphoid Leukemia Protein , Humans , Mice , Animals , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Gene Rearrangement , Mice, Transgenic , Cell Transformation, Neoplastic/pathology , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , DNA-Binding Proteins/metabolism , Transcription Factors/metabolism , RNA-Binding Proteins/genetics
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