Genomic Profiling of Pediatric B-cell Acute Lymphoblastic Leukemia

Pediatric leukemia is the most common type of childhood cancer and, despite tremendous progress in treatment, remains the second leading cause of cancer deaths in children. B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of pediatric leukemia. Recent studies using transcriptional profiling of large cohorts of pediatric B-ALL have shown that patients can be grouped into transcriptional subtypes that are often defined by specific driver mutations. Interestingly, many of these mutational subtypes are defined by gene fusions or rearrangements that drive altered expression of transcription factors (ETV6-RUNX1, PAX5, DUX4, TCF3-PBX1, ZNF384) or in chromatin regulatory machinery (KMT2A), suggesting that transcriptional dysregulation is a major driver of B-ALL. While the transcriptional distinctions are clear, the relationship between patients in terms of their chromatin regulatory landscape remains unclear. To address this, we profiled gene expression, open chromatin, and 3D genome folding in patient derived B-ALL samples. We identified that at the level of 3D genome organization, many chromatin interactions and looping events are shared across mutational subtypes, suggesting that shared transcriptional programs, in addition to group specific driver mutations, possibly regulate the chromatin landscape in B-ALL. Using RNA-seq and ATAC-seq data, we were able to identify "latent" signatures of expression related to non-mutant transcription factors (TFs) that also contribute to expression heterogeneity across TF subtypes. These are related to patient specific patterns of 3D genome folding, and in some cases, are predictive of disease outcomes. This study helps shed light on the chromatin landscape in B-ALL and furthers our understanding of the interactions between diverse mutant TFs that drive B-ALL and non-mutant TFs that help shape the B-ALL chromatin landscape.]]>
Our efforts to identify chromatin organization in leukemia samples will utilize patient derived samples from Rady Children's Hospital San Diego (RCHSD). This will require the use of children for this study. Leukemia is the most common type of pediatric cancer, and there are apparent differences in genetic makeup and clinical manifestations of the disease depending on a patients age. Therefore, studying the mechanisms that drive pediatric leukemia cannot be easily remedied by studying non-pediatric patients. Pediatric leukemia affects both males and females, and has no apparent differences in prevalence as a result of race or ethnicity. The patients for this study will be from RCHSD, and as a result will reflect the demographic patterns of the RCHSD patient population. No exclusion or inclusion criteria will be used for this study. Patients will be identified upon presentation for first diagnosis or relapse by members of the RCHSD oncology team. The patients will therefore likely be symptomatic due to their disease. RCHSD sees approximately 50-60 new diagnoses of leukemia each year and has between 10-20 relapse cases each year.]]>