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Updated: Oct 12, 2025
Mouse Fetal Liver Culture System to Dissect Target Gene Functions at the Early and Late Stages of Terminal Erythropoiesis
Published on: September 9, 2014
A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene
Siobhan Rice1, Thomas Jackson2, Nicholas T Crump1
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Insights
Infant acute lymphoblastic leukemia (ALL) driven by MLL-AF4 maintains fetal gene programs, unlike childhood ALL. This cooperation explains the aggressive nature of infant ALL.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Prognosis for infant acute lymphoblastic leukemia (ALL) remains poor despite high cure rates in older children.
- Infant ALL is characterized by MLL/KMT2A gene rearrangements (MLL-r), often occurring in utero.
- The molecular basis for the aggressive nature and treatment resistance of infant ALL compared to childhood ALL with identical MLL-r is not understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the distinct aggressive phenotype of infant ALL.
- To determine if fetal-specific gene expression programs contribute to the pathogenesis of infant ALL.
- To establish a model system for studying infant ALL driven by the common MLL-AF4 translocation.
Main Methods:
- Utilized MLL-AF4 as a disease model for infant ALL.
- Employed CRISPR-Cas9 gene editing in primary human fetal liver hematopoietic cells to create the t(4;11)/MLL-AF4 translocation.
- Analyzed gene expression profiles in infant ALL, childhood ALL, and engineered cells.
Main Results:
- MLL-AF4 infant ALL samples maintain fetal-specific gene expression programs.
- MLL-AF4 childhood ALL samples do not exhibit these fetal gene expression programs.
- Engineered t(4;11)/MLL-AF4 translocation replicated infant ALL features and induced fetal-specific gene expression.
Conclusions:
- Fetal-specific gene expression programs are retained in infant ALL.
- These programs cooperate with the MLL-AF4 translocation to drive the unique biology and aggressive course of infant ALL.
- Understanding these mechanisms may reveal new therapeutic targets for infant ALL.
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.
