Advances in the genetics of high-risk childhood B-progenitor acute lymphoblastic leukemia and juvenile myelomonocytic leukemia: implications for therapy

Abstract

Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereas MPN is associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlap MPN/MDS found exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed.