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

Siobhan Rice, Thomas Jackson, Nicholas T. Crump, Nicholas Fordham, Natalina Elliott, Sorcha O’Byrne, Maria del Mar Lara Fanego, Dilys Addy, Trisevgeni Crabb, Carryl Dryden, Sarah Inglott, Dariusz Ladon, Gary Wright, Jack Bartram, Philip Ancliff, Adam J. Mead, Christina Halsey, Irene Roberts, Thomas A. Milne () and Anindita Roy ()
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Siobhan Rice: University of Oxford
Thomas Jackson: University of Oxford
Nicholas T. Crump: University of Oxford
Nicholas Fordham: University of Oxford
Natalina Elliott: University of Oxford
Sorcha O’Byrne: University of Oxford
Maria del Mar Lara Fanego: Great Ormond Street Hospital for Children
Dilys Addy: Great Ormond Street Hospital for Children
Trisevgeni Crabb: Great Ormond Street Hospital for Children
Carryl Dryden: Great Ormond Street Hospital for Children
Sarah Inglott: Great Ormond Street Hospital for Children
Dariusz Ladon: Great Ormond Street Hospital for Children
Gary Wright: Great Ormond Street Hospital for Children
Jack Bartram: Great Ormond Street Hospital for Children
Philip Ancliff: Great Ormond Street Hospital for Children
Adam J. Mead: University of Oxford
Christina Halsey: University of Glasgow
Irene Roberts: University of Oxford
Thomas A. Milne: University of Oxford
Anindita Roy: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27270-z

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