A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.
Animals
CRISPR-Cas Systems
DNA-Binding Proteins
Female
Fetus
Gene Editing
Gene Expression Regulation, Neoplastic
Histone-Lysine N-Methyltransferase
Humans
Liver
Mice
Myeloid-Lymphoid Leukemia Protein
/ genetics
Oncogene Proteins, Fusion
/ genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Transcriptional Elongation Factors
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 11 2021
25 11 2021
Historique:
received:
19
11
2020
accepted:
08
11
2021
entrez:
26
11
2021
pubmed:
27
11
2021
medline:
4
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34824279
doi: 10.1038/s41467-021-27270-z
pii: 10.1038/s41467-021-27270-z
pmc: PMC8616957
doi:
Substances chimiques
DNA-Binding Proteins
0
KMT2A protein, human
0
MLL-AF4 fusion protein, human
0
Oncogene Proteins, Fusion
0
Transcriptional Elongation Factors
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
AFF1 protein, human
150826-18-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
6905Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust (Wellcome)
ID : 216632/Z/19/Z
Organisme : Wellcome Trust
ID : 099175/Z/ 12/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00016/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/14
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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