Introduction

Although most cases of acute lymphoblastic leukemia (ALL) do not arise from a recognized predisposing genetic condition, this disease is still considered to have a genetic basis. That is, somatically acquired genetic changes contribute in pivotal ways to the genesis of ALL and have important implications for its diagnosis and treatment. Such acquired lesions, restricted to the leukemic clone, include alterations in both the number (ploidy) and structure of the blast cell chromosomes, the latter consisting of reciprocal translocations, inversions, deletions, gene amplifications, and point mutations. Although many of these abnormalities can be detected by routine cytogenetic analysis, others require molecular assays. Molecular identification of the genetic targets of these alterations has led to the isolation and characterization of numerous oncogenes and tumor suppressors, providing valuable clues to the mechanisms of leukemogenesis. In this chapter, we review the molecular basis of childhood ALL, emphasizing the oncogenes, oncoproteins, and tumor suppressors that appear to be critical components of a limited number of transforming pathways.

Proto-oncogene activation

Standard karyotyping can identify chromosomal translocations, including both recurrent and random rearrangements, in about 50% of cases of childhood ALL. When molecular assays are used with cytogenetic analysis, evidence of a translocation is seen in about 70% of cases (Fig. 10.1). Translocations in ALL most often disrupt genes that encode transcription factors (Tables 10.1 and 10.2), defined as nuclear proteins that bind to DNA and regulate the expression of other cellular proteins.