Introduction

Childhood acute lymphoblastic leukemia (ALL) has served as a model for cancer research and treatment for at least six decades. With more precise diagnostic criteria and risk classifications, more effective therapy administered in controlled clinical trials, and better supportive care, the outlook for children with ALL has improved dramatically. Today, 80 to 90% of children treated for this disease in developed countries will be cured. Remarkably, this high cure rate has been achieved mainly by optimizing risk-directed therapy, using drugs that were discovered before 1980. Because of the ease with which samples of leukemic lymphoblasts can be obtained from the bone marrow and blood, laboratory studies of childhood ALL have consistently been at the fore of efforts to elucidate the principles of cancer cell biology and to boost therapeutic results still further. This chapter seeks to integrate key advances in the biologic understanding of ALL with accepted principles of clinical management.

Pathogenesis and pathophysiology

Leukemic transformation of hematopoietic cells requires subversion of the controls of normal proliferation, a block in differentiation, resistance to apoptotic signals, and enhanced self-renewal. The prevailing theory of leukemia pathogenesis is that a single mutant hematopoietic cell, capable of indefinite self-renewal, gives rise to malignant, poorly differentiated hematopoietic precursors. Although leukemic transformation may occur in a stem cell, it more likely arises from a more differentiated cell that acquires stem-cell-like properties. Several lines of research support the clonal origin of leukemia, including glucose-6-phosphate dehydrogenase studies and recombinant DNA analysis based on X-linked restriction fragment length polymorphisms in heterozygous females (whose normal tissues have a mosaic pattern of X chromosome expression yet whose leukemic cells show a single active parental allele).