KMT2A-rearranged (KMT2A-r) baby acute lymphoblastic leukemia (ALL) has a poor prognosis, and lower age at diagnosis is associated with an increased risk of recurrence. For a study, researchers performed single-cell multi-omics analysis on KMT2A-r leukemias and normal hematopoietic cells from patients of various ages to identify age-specific changes and important drivers that underlie poor prognosis in KMT2A-r ALL.

They discovered the following important new insights: Six-month-old leukemia cells have dramatically greater lineage plasticity. In the most immature blasts from younger patients, steroid response pathways are downregulated. In the blood of younger patients, they found a hematopoietic stem and progenitor-like (HSPC-like) population that comprises leukemic blasts and forms an immunosuppressive signaling circuit with cytotoxic cells. 

The findings provided a persuasive explanation for leukemias in young patients’ propensity to resist chemotherapy and immune-mediated control. At the time of B-ALL diagnosis, the study indicated preexisting lymphomyeloid primed progenitors and myeloid blasts. The tracking of leukemic clones in two patients whose leukemia underwent a lineage transition revealed that such clones evolved into frank acute myeloid leukemia (AML). 

The findings provided light on KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy treatments. Beyond baby ALL, the findings showed that single-cell multi-omics may identify tumor intrinsic and extrinsic variables impacting uncommon but crucial subpopulations within a malignant population, which ultimately decides patient prognosis.