The present study was focused on leukemia bilineality is triggered by a subclonally derived genetic aberration driving the transdifferentiation or reprogramming of individual subclones and transforming leukemia that was originally uniform into bilineal leukemias. High-throughput genomic methods to analyze the genomic landscape of immunophenotypically distinct subpopulations in 2 bilineal leukemia patients, whole transcriptome sequencing and whole exome sequencing in addition, bulk leukemic samples were analyzed with whole genome single nucleotide polymorphism arrays. Single nucleotide polymorphism arrays detected copy number aberrations in MTAP, CDKN2A, and CDKN2B genes and uniparental disomy was associated with bilineal leukemia and acute lymphoblastic leukemia patients. Immunophenotypically heterogeneous leukemic populations derived from an identical founder cell, but multiple leukemic cells possess the potential to differentiate into very distinct cell types.