SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming

Infant leukemias arise as B-cell acute lymphoblastic or acute myeloid leukemia. Most are driven by chromosomal rearrangements of the <i>MLL</i>/<i>KMT2A</i> gene (MLLr) and arise in utero, implying a fetal cell of origin. Fetal and neonatal hematopoietic progenitors have unique transcriptomes and epigenomes, raising the question of whether MLL fusion proteins activate distinct target genes during these early stages of life. In this study, we used a transgenic mouse model of MLL::ENL-driven leukemia to identify <i>Skida1</i> as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors. <i>SKIDA1</i> is highly expressed in human MLLr leukemias, and the encoded protein associates with the polycomb repressive complex 2. We show that <i>Skida1</i> is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells during neonatal development. Conditional deletion of <i>Skida1</i> has no effect on normal HSC function, yet it impairs B-cell production from neonatal MLL::ENL-expressing HSCs while leaving myeloid leukemogenesis unaffected. Temporally restricted targets of MLL fusion proteins, such as <i>SKIDA1</i>, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.