TY - JOUR
T1 - A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia
AU - Eldeeb, Mohamed
AU - Yuan, Ouyang
AU - Guzzi, Nicola
AU - Thi Ngoc, Phuong Cao
AU - Konturek-Ciesla, Anna
AU - Kristiansen, Trine A.
AU - Muthukumar, Sowndarya
AU - Magee, Jeffrey
AU - Bellodi, Cristian
AU - Yuan, Joan
AU - Bryder, David
N1 - Funding Information:
We acknowledge Roberto Munita, Maciej Ciesla, Leal Oburoglu, Hugo Åkerstrand, and Pekka Jaako for valuable scientific discussions and technical support. Some of the results shown here are based on data generated by the TCGA Research Network: https://www.cancer.gov/tcga . J.M. is a Leukemia and Lymphoma Society scholar. The work was supported by grants from the Tobias Foundation , the Swedish Cancer Foundation , the Knut and Alice Wallenberg foundation, Swedish Childhood Cancer foundation and the Swedish Research Council . The authors declare no competing financial interests.
Funding Information:
We acknowledge Roberto Munita, Maciej Ciesla, Leal Oburoglu, Hugo Åkerstrand, and Pekka Jaako for valuable scientific discussions and technical support. Some of the results shown here are based on data generated by the TCGA Research Network: https://www.cancer.gov/tcga. J.M. is a Leukemia and Lymphoma Society scholar. The work was supported by grants from the Tobias Foundation, the Swedish Cancer Foundation, the Knut and Alice Wallenberg foundation, Swedish Childhood Cancer foundation and the Swedish Research Council. The authors declare no competing financial interests. M.E. designed the research, performed experiments, analyzed data, and wrote the manuscript; O.Y. and S.M. performed experiments; N.G. and C.B. designed and performed the iCLIP-seq, and P.C.T.N. and A.K-C. performed the bioinformatic analysis; J.Y. provided access to the Lin28B-related reagents; J.M. provided key input and protocols for CAS9-RNP experiments; T.K. J.Y. and J.M. contributed to the discussion. D.B. supervised the project, was responsible for funding acquisition, designed the research, analyzed data, and wrote the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/2/28
Y1 - 2023/2/28
N2 - 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.
AB - 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.
KW - AML
KW - CP: Cancer
KW - LIN28B
KW - MLL-rearrangements
KW - MYB
KW - MYBBP1A
KW - hematopoiesis
KW - leukemia-initiating cell
KW - ontogeny
KW - tumor suppression
UR - http://www.scopus.com/inward/record.url?scp=85147712118&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.112099
DO - 10.1016/j.celrep.2023.112099
M3 - Article
C2 - 36763502
AN - SCOPUS:85147712118
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 2
M1 - 112099
ER -