Proposed schema for the role of genetic alterations in the pathogenesis of B-ALL. It is likely that chromosomal rearrangements are acquired early in leukemogenesis and drive transcriptional and epigenetic dysregulation and aberrant self-renewal. These lesions and/or secondary genetic alterations disrupt lymphoid development and result in an arrest in maturation. Additional genetic alterations target multiple cellular pathways, including cell-cycle regulation, tumor suppression, and chromatin modification. In a subset of cases (BCR-ABL1⁺ and BCR-ABL1–like ALL), genetic alterations drive aberrant cytokine receptor and kinase signaling. Together, these events result in the proliferation and establishment of the leukemic clone. Diagnosis ALL samples are commonly clonally heterogeneous, and genetic alterations in minor clones may confer resistance to therapy and promote disease relapse. It should be noted that a direct role of many of the genetic alterations shown in the pathogenesis of ALL has not yet been confirmed experimentally. A similar schema can be proposed for T-ALL, in which lesions targeting lymphoid development, self-renewal, and kinase signaling are also observed and in which there are multiple targets of mutations with unknown roles in leukemogenesis (eg, PHF6 and WT1).