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

ABSTRACT

Infant leukemias arise as B-cell acute lymphocytic (B-ALL) or acute myeloid leukemia (AML). The majority are driven by chromosomal rearrangements of theMLL/ KMT2Agene (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 gene profiles during these early stages of life. Here, we use a transgenic mouse model of MLL::ENL-driven leukemia to identifySkida1as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors.SKIDA1is highly expressed in humanMLLr leukemias and the protein associates with the Polycomb Repressive Complex 2 (PRC2). We show thatSkida1is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) during neonatal development. Conditional deletion ofSkida1has 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 SKIDA1, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.