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

Mohamed Eldeeb, Ouyang Yuan, Nicola Guzzi, Phuong Cao Thi Ngoc, Anna Konturek-Ciesla, Trine A. Kristiansen, Sowndarya Muthukumar, Jeffrey Magee, Cristian Bellodi, Joan Yuan, David Bryder

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Article number112099
JournalCell Reports
Volume42
Issue number2
DOIs
StatePublished - Feb 28 2023

Keywords

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

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