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. 2023 Feb 28;42(2):112099.
doi: 10.1016/j.celrep.2023.112099. Epub 2023 Feb 9.

A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia

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Free article

A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia

Mohamed Eldeeb et al. Cell Rep. .
Free article

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.

Keywords: AML; CP: Cancer; LIN28B; MLL-rearrangements; MYB; MYBBP1A; hematopoiesis; leukemia-initiating cell; ontogeny; tumor suppression.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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