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Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease with multiple distinct biological subtypes.
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High-throughput genomic profiling and next-generation sequencing technologies have identified submicroscopic genomic lesions and sequence mutations that define novel subtypes of ALL.
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The discovery of various oncogenic pathways and candidate genes has led to the development of biologically based targeted therapy.
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Host germline polymorphisms influence susceptibility to ALL,
Biology of Childhood Acute Lymphoblastic Leukemia
Section snippets
Key points
B-cell acute lymphoblastic leukemia
Eighty-five percent of the cases of childhood ALL are of the B-cell lineage (B-ALL). To keep pace with the growing impact of biological findings on treatment outcomes, in 2008 the World Health Organization revised the nomenclature from solitary precursor B-ALL to a classification based on 7 specific, recurring genetic lesions (eg, B-ALL with ETV6-RUNX1, B-ALL with hyperdiploidy).6 Of note, the term B-ALL is not used for Burkitt leukemia/lymphoma, which is a mature B-cell malignancy. As newer
BCR-ABL–Like Acute Lymphoblastic Leukemia
IKZF1 deletions are a hallmark of BCR-ABL1–positive ALL, but these deletions also occur in a subset of patients with poor-response, high-risk ALL without any known chromosomal rearrangement.18 Using genome-wide analyses, 2 groups of investigators independently identified a subgroup of B-ALL, which has a gene-expression profile similar to that of BCR-ABL1–positive ALL including a high frequency of IKZF1 alterations, but lacks the BCR-ABL1 fusion protein; they termed this genetic subtypes
T-cell acute lymphoblastic leukemia
T-ALL accounts for 10% to 15% of the cases of childhood ALL. The outcome of children with T-ALL, which has been historically poor, has improved gradually with the use of intensified therapy, including dexamethasone, asparaginase, and high-dose methotrexate.3, 8 However, children who relapse have a dismal outcome even with hematopoietic stem cell transplantation.32 Therefore, it is critical to identify aberrant molecular pathways and targets for therapeutic intervention for T-ALL. Genetic
Epigenetics in acute lymphoblastic leukemia
In recent years, the importance of epigenetic regulatory mechanisms in normal and malignant hematopoiesis has become increasingly evident. Alterations in the methylation of DNA promoters and the modification of histones can significantly perturb transcriptional regulation and modify gene expression. Different subtypes of ALL are characterized by distinct DNA methylation signatures, which in turn correlate with gene expression profiles.15 Several genes related to lymphoid development that are
Biology of relapsed acute lymphoblastic leukemia
Studies of matched diagnosis-relapse samples have shed light on the clonal evolution leading to relapse, pathways associated with chemoresistance, and potential targets for therapy. In one study, 86% of the patients at relapse had outgrowth of a minor subclone present at diagnosis, which had genetic alterations both similar to and different from the major clone at diagnosis.46 In some patients, relapse may have genetic alterations either identical to or entirely different from those seen at
Acute Lymphoblastic Leukemia Susceptibility
Besides constitutional trisomy 21 (Down syndrome) and rare DNA damage repair defects (eg, ataxia-telangiectasia and Bloom syndrome), little is known about the genetic predisposition to ALL.54 The frequency of hematologic malignancies is 4% in patients with common cancer predisposition syndromes such as Li-Fraumeni syndrome (caused by inherited mutations in TP53), approximately half of which are ALL.55 However, a study of hypodiploid ALL with whole-genome and whole-exome sequencing revealed that
Summary
Modern-day management of childhood ALL exemplifies the successful integration of biology into therapeutic decision making. In addition to the prognostic impact of conventional chromosomal translocations and aneuploidy, functional studies of key genetic alterations have contributed to our understanding of ALL pathogenesis. With the advent of high-throughput genomics and NGS technologies, knowledge of specific molecular lesions and critical pathways of leukemogenesis has exponentially increased.
Acknowledgments
The authors thank Klo Spelshouse (Department of Biomedical Communications, St. Jude Children’s Research Hospital) for assistance with illustrations, and Vani Shanker (Department of Scientific Editing, St. Jude Children’s Research Hospital) for assistance with editing the article.
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Funding: National Institutes of Health grant P30-CA021765 and the American Lebanese Syrian Associated Charities.