We report a case with multiple lineage switches, a rare event that mostly occurred in infants, in a ten-year-old girl with KMT2A-AFF1 positive ALL. Although she received standard chemotherapy, immunotherapy and hematopoietic stem cell transplantation (HSCT), the leukemic clone continuously switched on AML or ALL, maintaining immunoglobulin/T-cell receptor (IG/TR) rearrangements and showing a high grade of therapy-escaping. Since other genes are involved in this event, considering the selective pressure imposed by the applied treatment, it is mandatory to characterize the cell-of-origin that is capable to proliferate towards both lineages in the attempt to design a targeted therapy.