Co-option of lineage plasticity as a hallmark of multipotent acute leukemias

Leukemias are classified by hematopoietic lineage and genetic alterations. Mixed-lineage and biphenotypic leukemias have long challenged diagnostic classification because of the coexpression of markers of distinct lineages. Recent studies have revealed previously unappreciated multilineage potential in a subset of B-cell acute lymphoblastic leukemias (B-ALL) as well as leukemias with markers of myeloid and T-cell differentiation with shared genetic features variably classified as acute myeloid leukemia, early T-cell progenitor ALL, or T/myeloid mixed-phenotype acute leukemias. We propose that co-option of stem cell plasticity programs can be used to classify these as multipotent acute leukemias (MAL). Based on the urgent need for improved diagnostic and therapeutic strategies, we review the latest evidence and propose new ways to diagnose and treat MAL as distinct types of acute leukemias.