Genomic Profiling of Acute Lymphoblastic Leukemia: Insights Into Pathogenesis, Prognosis, and Therapeutic Targets.
Authors: Mullighan Charles G. 
Published: October 2019

Abstract
Abstract SCI-29
Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, and an important cause of morbidity in adults. ALL is characterized by recurring gross chromosomal alterations including aneuploidy and translocations, but these abnormalities are usually insufficient to cause leukemia, and do not explain the spectrum of clinical manifestations and disease behaviour in ALL. A substantial proportion of patients with ALL fail therapy, and the biologic determinants of relapse are incompletely understood. To better understand the genetic basis of leukemogenesis and treatment outcome in ALL, several groups have performed high resolution, genome-wide analyses of genetic alterations in leukemic cells obtained at diagnosis and relapse. These studies have identified multiple novel recurring submicroscopic genetic alterations in leukemic samples obtained at diagnosis that target critical cellular pathways including lymphoid development, cell cycle regulation, tumor suppressors, apoptosis, and drug responsiveness. Notably, over 60% of B-progenitor ALL cases harbor genetic alterations targeting lymphoid development (most commonly transcription factors including PAX5, IKZF1, EBF1, and LEF1). Recent data from experimental models have shown that these lesions contribute to leukemogenesis, and that acquisition of the full leukemic phenotype is accompanied by the sequential acquisition of multiple genetic lesions targeting different cellular pathways. Recent studies have examined genetic determinants that influence treatment outcome, and have examined the evolution of genetic alterations during disease progression. Notably, mutation of the early lymphoid transcription factor IKZF1 (IKAROS) is characteristic of multiple subtypes of high risk ALL. Deletion of IKZF1 is very common in de novo BCR-ABL1 positive ALL, and at the progression of chronic myeloid leukemia to lymphoid blast crisis. Moreover, IKZF1 is associated with poor prognosis in BCR-ABL1 negative ALL. A proportion of IKZF1 deleted, BCR-ABL1 negative ALL cases share a similar gene expression profile to BCR-ABL1 positive ALL, and candidate gene resequencing has identified activating mutations of Janus kinases (JAK1, JAK2 and JAK3) in a proportion of these cases, suggesting that JAK-STAT inhibition may be a useful therapeutic approach. Careful comparison of the patterns of genetic alteration in matched diagnosis and relapse leukemia samples have shown that the burden of genetic lesions in ALL is not static, but evolves during therapy. Notably, over 90% of ALL cases show differences in the pattern of genetic lesions between diagnosis and relapse. Rather than simple clonal evolution, in more than 50% of cases, lesions identified at diagnosis are lost at relapse, as well as new lesions gained, but with genetic evidence of a common clonal origin of the diagnosis and relapse clones. Backtracking of relapse-acquired lesions has shown that the relapse clone is frequently present at low levels at diagnosis. This indicates that in the majority of patients, multiple disease clones are present at diagnosis, and the complement of genetic alterations in each subclone strongly influences treatment response. These studies have provided valuable insights into the genetic complexity of ALL, and have provided important insights into the pathogenesis of this disease, as well as highlighting potential pathways for therapeutic intervention. Future challenges include comparably detailed analysis of adult ALL, and incorporation of additional genetic profiling platforms, including epigenetic analysis, and genome-wide analysis of sequence variation.

Disclosures
No relevant conflicts of interest to declare.