Abstract

Leukemia initiating cells (LICs) fuel leukemic growth and spark relapse. Previously thought to be primitive and rare, the LIC state may actually be heterogeneous and dynamic, enabling evasion of therapies. Here, we use single-cell transcriptomics to track LIC multipotency within the cellular ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL). Although we identify rare transcriptionally and phenotypically primitive LICs, we also observe LICs emerging from more differentiated populations with the capability to replenish the full leukemic cellular diversity. We find that activation of MYC-driven oxidative phosphorylation controls this process of facultative state conversion in LICs.