Summary Infant ALL is a devastating malignancy caused by rearrangements of the KMT2A gene ( KMT2A-r ) in approximately 70% of patients. The outcome is dismal and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate the poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to multi-omic single cell analysis using scRNA-Seq, scATAC-Seq and snmC-Seq2. We uncovered the following critical new insights: Leukemia cells from infants younger than 6 months have a greatly increased lineage plasticity and contain a hematopoietic stem and progenitor-like (HSPC-like) population compared to older infants. We identified an immunosuppressive signaling circuit between the HSPC-like blasts and cytotoxic lymphocytes in younger patients. Both observations offer a compelling explanation for the ability of leukemias in young infants to evade chemotherapy and immune mediated control. Our analysis also revealed pre-existing lymphomyeloid primed progenitor and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in two patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank AML. These findings provide critical insights into KMT2A-r ALL and have potential clinical implications for targeted inhibitors or multi-target immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single cell multi-omics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.