Infant leukemia associated with rearrangement of the MLL gene typically presents with high-risk clinical features. Relapse is common despite aggressive therapy and perturbations in signaling pathways may contribute to disease resistance. We evaluated twin 4-month-old monozygotic baby boys who presented with MLL-rearranged precursor-B acute lymphoblastic leukemia. Two different MLL/AF4 variants were found in both the twins, the first involving MLL intron 8 and AF4 intron 3 and the second stemming from translocations of MLL exon 10 and AF4 exon 4. We detected expression of the DNA-binding Ikaros isoforms, Ik1, Ikx+, Ik2 and the dominant-negative Ik4 Ikaros isoform in both patients. However, the dominant-negative Ik8 isoform was detected in only 1 boy, suggesting a common genetic ontogeny that was modulated by leukemic evolution. Further exploration of Ikaros expression in the background of MLL rearrangements may provide new insights into disease pathogenesis and could offer targets for novel chemotherapeutic agents.