Abstract SY25-04: Sequencing the genome of acute lymphoblastic leukemia
Authors: Mullighan Charles G. 
Published: August 2012

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, and remains the leading cause of non-traumatic death in children and young adults. Current treatment of ALL utilizes combination systemic and intrathecal therapy with mostly non-targeted chemotherapeutic agents, and further escalation of treatment intensity is limited by unacceptable short- and long term toxicity. Targeted therapy with tyrosine kinase inhibitors in BCR-ABL1 positive leukemia has been dramatically successful, and this observation has stimulated intense interest in identifying rational targets for novel therapies in additional patients with ALL. Moreover, ALL has long been known to consist of a number of subtypes characterized by distinct constellations of genetic alterations defined by karyotypic analysis, microarray profiling and candidate gene sequencing, including structural chromosomal rearrangements, DNA copy number alterations and DNA sequence mutations. While these approaches have been informative in identifying novel somatic genetic alterations in ALL, they are inherently incapable of comprehensively identifying all and somatic genetic alterations driving leukemogenesis and influencing treatment outcome. In addition, these approaches have limited ability to fully characterize the nature of intratumoral clonal heterogeneity and genetic diversity, which is now recognized to be a hallmark of ALL, and an important determinant of treatment failure and relapse.

Several groups are now utilizing next-generation sequencing to provide a comprehensive portrait of the nature and frequency of inherited and somatic genetic alterations in ALL. These projects, including the St Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, and the National Cancer Institute - Children's Oncology Group TARGET (Therapeutically Applicable Research to Generate Effective Therapies) Initiative multi-institutional collaborative efforts that are using transcriptome sequencing (RNA-seq), exome sequencing and whole genome sequencing (WGS) of large numbers of ALL samples. Results and future directions for several of these projects will be described, and include:

(1) Early T-cell precursor (ETP) ALL: WGS of this aggressive leukemia has shown that ETP is characterized by frequent mutations in multiple critical cellular pathways, including hematopoetic development, cytokine receptor and Ras signaling, and epigenetic regulation of gene expression. These findings have identified several potential new approaches for therapy in ETP ALL.

(2) High risk “BCR-ABL1-like” B-progenitor ALL: This form of leukemia exhibits many features similar to BCR-ABL1 positive ALL, yet lacks expression of the BCR-ABL1 chimeric fusion protein. RNA-seq and WGS have identified a range of novel rearrangements, structural variations and sequence mutations that activate cytokine receptor and tyrosine kinase signaling. Importantly, these alterations are transforming, and potentially druggable with currently available tyrosine kinase inhibitors.

(3) Infant leukemia. Infant ALL is highly aggressive and commonly accompanied by rearrangement of the mixed lineage leukemia (MLL) gene. WGS of MLLr infant leukemia extends the findings of pre-WGS genomic profiling studies by showing that very few additional somatic genetic alterations are present in this form of ALL.

These studies have also stimulated the development of novel, sensitive and specific algorithms for the detection of structural genetic alterations described by Dr Zhang in this session, and notably, have shown that WGS and RNA-seq may provide complementary genetic information. Also, these studies have also shown that in addition to comprehensive characterization of “discovery” cohorts of leukemia genomes, detailed analysis of mutational frequency in extended recurrence cohorts, and complementary profiling of gene expression is required to accurately define the nature and frequency of genetic alterations across the range of ALL subtypes, and to assess their role in leukemogenesis. Importantly, these studies have largely focused on somatic genetic variation affecting coding genes, and a key goal of ongoing studies is the investigation of the role of inherited and somatic non-coding variation in leukemogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY25-04. doi:1538-7445.AM2012-SY25-04