Molecular profiling of myeloid/natural killer (NK) cell precursor acute leukemia

Abstract

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described based on its clinical phenotype and immunophenotype, and proposed as a unique leukemia entity. However, due to its rarity and lack of defined distinctive molecular characteristics, there is currently no international consensus on this disease concept. We performed multi-omics analysis and revealed that MNKPL is distinct from acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia. NOTCH1 and RUNX3 activation and BCL11B downregulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, our single-cell analysis using MNKPL cells suggested that NK cells and myeloid cells share common progenitor cells. Our retrospective case study uncovered that outcomes of MNKPL are unsatisfactory, even with hematopoietic cell transplantation. Multi-omics analysis and in vitro drug sensitivity assays revealed increased sensitivity to L-asparaginase and reduced levels of asparagine synthetase, supporting the clinically observed effectiveness of L-asparaginase.