Molecular Genetics of Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is mainly a disease of childhood that arises from recurrent genetic insults that block precursor B and T cell differentiation and drive aberrant cell proliferation and survival. Recurrent defects including chromosomal translocations, aneuploidies, and gene-specific alterations generate molecular subgroups of B- and T-ALL with differing clinical courses and distinct responses to therapy. Recent discoveries arising from genome-wide surveys and adoptive transfer of leukemia-initiating cells have uncovered multiple gene copy number aberrations and have yielded new insight into at least one type of ALL-originating cell. Our understanding of the pathogenesis of ALL has benefited from genetically modified mouse models that recapitulate cellular transformation at specific developmental stages of lymphoid lineage cells. Here, we review the spectrum of genetic aberrations that promote acute B and T cell leukemias and the mechanisms of cell transformation and malignant progression that are reinforced by mouse models of human ALL.