GSE162032
A novel human fetal model of infant ALL reveals a link between MLL-AF4, PAF1 and increased H3K79me2/3 [RNA-seq]
Acute Lymphoblastic Leukemia (ALL) caused by chromosomal translocation involving the Mixed Lineage Leukemia (MLL) gene remains a poor prognosis disease, especially in infants. The most common MLL-rearrangement in infant ALL (iALL), MLL-AF4, originates in utero where the properties of fetal target cells likely provide a permissive landscape for transformation. We describe the first faithful MLL-AF4 iALL model derived by CRISPR-Cas9 genome editing of primary human fetal liver (FL) cells. Using this model, we demonstrate that H3K79me2/3 is increased during transformation as a direct consequence of MLL-AF4 binding, but correlates weakly with changes in gene expression. DOT1L, the only known H3K79 methyltransferase, does not form part of the MLL-AF4 complex. Instead, we identify PAF1 as a key protein recruited by the MLL-AF4 complex, which in turn can recruit DOT1L. These results explain the previously unclear link between MLL-AF4 binding and increased H3K79me2/3, and introduce an iALL-specific model for future drug studies. Overall design: RNA-seq