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

Eldeeb, Mohamed LU ; Yuan, Ouyang LU ; Guzzi, Nicola LU ; Thi Ngoc, Phuong Cao LU ; Konturek-Ciesla, Anna LU ; Kristiansen, Trine A. LU ; Muthukumar, Sowndarya LU ; Magee, Jeffrey ; Bellodi, Cristian LU and Yuan, Joan LU orcid , et al. (2023) In Cell Reports 42(2).
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.... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AML, CP: Cancer, hematopoiesis, leukemia-initiating cell, LIN28B, MLL-rearrangements, MYB, MYBBP1A, ontogeny, tumor suppression
in
Cell Reports
volume
42
issue
2
article number
112099
publisher
Cell Press
external identifiers
  • pmid:36763502
  • scopus:85147712118
ISSN
2211-1247
DOI
10.1016/j.celrep.2023.112099
language
English
LU publication?
yes
id
46d93f17-2b3a-417c-9a8a-f8fe5b9d09f1
date added to LUP
2023-02-20 15:34:48
date last changed
2024-04-18 10:24:06
@article{46d93f17-2b3a-417c-9a8a-f8fe5b9d09f1,
  abstract     = {{<p>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.</p>}},
  author       = {{Eldeeb, Mohamed and Yuan, Ouyang and Guzzi, Nicola and Thi Ngoc, Phuong Cao and Konturek-Ciesla, Anna and Kristiansen, Trine A. and Muthukumar, Sowndarya and Magee, Jeffrey and Bellodi, Cristian and Yuan, Joan and Bryder, David}},
  issn         = {{2211-1247}},
  keywords     = {{AML; CP: Cancer; hematopoiesis; leukemia-initiating cell; LIN28B; MLL-rearrangements; MYB; MYBBP1A; ontogeny; tumor suppression}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2023.112099}},
  doi          = {{10.1016/j.celrep.2023.112099}},
  volume       = {{42}},
  year         = {{2023}},
}