Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Abstract

Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches. (Blood. 2015;125(26):3977-3987)

Routine Cytogenetic Analysis of Chromosome Abnormalities in Acute Lymphoblastic Leukemia

“…Cytogenetic and molecular cytogenetic studies revealed chromosomal abnormalities in only about 80% of ALL [42]. However, genome-wide studies utilizing microarraybased techniques and next-generation sequencing (NGS) have shown that most ALL harbour sequence and structural DNA alterations involving coding genes and noncoding elements such as noncoding RNAs and enhancer elements [43]. These genetic alterations affect key cellular pathways in lymphoid development, tumor suppression, cell cycle regulation, cytokine receptor, ras signaling and chromatin modifications.…”

The Role of Hematopoietic Stem-Cell Transplantation in First Remission in Pediatric Acute Lymphoblastic Leukemia: A Narrative Review

“…At the same time, new discoveries of high-risk (HR) ALL biology has been reported, for which conventional chemotherapy does not appear to cure. Examples of these new lesions with poor prognostic findings include deletions in IKZF1 (IKAROS), rearrangements of CRLF2, and ABL class fusions (6,7). Taken together, these lesions in part comprise the new prognostic group of HR leukemia identified as Philadelphia-Like (Ph-Like) B-ALL (7).…”

The origin of relapse in pediatric T-cell acute lymphoblastic leukemia

“…Over the last decade, studies using gene expression profiling, DNA copy-number analyses, and next-generation sequencing have provided new insights into the pathogenesis and clinical behavior of ALL. 4 Furthermore, sequencing studies of matched diagnostic, remission and relapse samples have provided important insights into the correlation of the different mutations, clonal evolution, and treatment resistance. 4 Using single nucleotide polymorphism array technology, Charles Mullighan and colleagues performed genomewide copy number analysis and loss-of-heterozygosity (LOH) analysis on matched diagnostic and relapse pediatric ALL samples.…”

“…4 Furthermore, sequencing studies of matched diagnostic, remission and relapse samples have provided important insights into the correlation of the different mutations, clonal evolution, and treatment resistance. 4 Using single nucleotide polymorphism array technology, Charles Mullighan and colleagues performed genomewide copy number analysis and loss-of-heterozygosity (LOH) analysis on matched diagnostic and relapse pediatric ALL samples. 5 They observed a significant increase in the number of chromosomal deletions in B-ALL samples taken at relapse, but no significant changes were observed in T-ALL.…”