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A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program

Title: A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
Authors: Rice, S
Jackson, T
Crump, NT
Fordham, N
Elliott, N
O'Byrne, S
Fanego, MDML
Addy, D
Crabb, T
Dryden, C
Inglott, S
Ladon, D
Wright, G
Bartram, J
Ancliff, P
Mead, AJ
Halsey, C
Roberts, I
Milne, TA
Roy, A
Item Type: Journal Article
Abstract: Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.
Issue Date: 25-Nov-2021
Date of Acceptance: 8-Nov-2021
URI: http://hdl.handle.net/10044/1/107853
DOI: 10.1038/s41467-021-27270-z
ISSN: 2041-1723
Publisher: Nature Portfolio
Journal / Book Title: Nature Communications
Volume: 12
Copyright Statement: © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Publication Status: Published
Article Number: 6905
Online Publication Date: 2021-11-25
Appears in Collections:Department of Immunology and Inflammation



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