Identifying the spectrum of genetic alterations in high risk ALL

St. Jude Children'S Research Hospital, Memphis TN

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Abstract

DESCRIPTION (provided by applicant): The goal of this project is to use contemporary genomic profiling approaches to identify genetic alterations contributing to the pathogenesis and treatment outcome of high risk acute leukemia. Despite best current therapy, acute lymphoblastic leukemia remains a leading cause of cancer- related death in young people, and commonly has a poor outcome in adults. New treatments directed against rational therapeutic targets are urgently required to improve the outcome of high risk leukemia. Our recent genomic analyses have identified a number of new mutations targeting key cellular growth and differentiation pathways in ALL that contribute to the leukemogenesis, predict outcome, and serve as targets for novel therapies. However, the genetic basis of several subtypes of high-risk leukemia remains poorly understood, including BCR-ABL1 (Philadelphia chromosome) positive leukemia, ALL with low hypodiploidy, and B- progenitor ALL cases lacking recurring cytogenetic alterations. BCR-ABL1 is a hallmark of chronic myeloid leukemia and a subset of acute leukemia, but the genetic alterations that determine the lineage of BCR-ABL1 disease, disease progression and response to therapy are poorly understood. Low hypodiploidy - the loss of multiple whole chromosomes - is associated with very poor outcome in ALL, but until recently detailed genomic analyses of this disease have been lacking. Furthermore, despite recent advances in our understanding of the genetics of ALL, a substantial minority of cases lack recurring cytogenetic alterations and fail therapy, and the basis of resistance to treatment in these cases is unknown. The key barriers to a better understanding of these conditions have been the lack of large cohorts of patient samples with detailed clinical data, and the lack of high-resolution, genome-wide platforms to comprehensively identify all genetic alterations in cancer. Here we will use complementary genomic profiling approaches, including microarray analysis of gains and losses of DNA, candidate gene resequencing, and next generation sequencing of tumor cell RNA ("transcriptomic resequencing") to identify genetic alterations in these diseases, and to examine associations with treatment outcome and disease progression. These genomic studies will be complemented by detailed experimental analysis of the effect of genetic alterations on signaling pathways within leukemic cells. Together, these approaches offer an important opportunity to improve our understanding and the treatment outcome of some of the clinically most problematic types of leukemia. PUBLIC HEALTH RELEVANCE: This project will use cutting-edge genomic technologies to examine the genetic basis of several types of high- risk leukemia. Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. Despite favorable overall cure rates, treatment failure and relapse ALL remains a leading cause of childhood cancer death. Our recent genomic profiling studies in ALL have demonstrated the power of these approaches to find new genetic alterations in leukemia that are associated with the development of the disease, and changes that predict treatment outcome and identify new targets for therapy. Several leukemia subtypes that have a high risk of relapse remain poorly studied. This project will examine leukemias harboring the Philadelphia chromosome (BCR-ABL1), low hypodiploid ALL, and ALL cases lacking changes on conventional cytogenetic analysis. We aim to detect new genetic changes, and also examine associations between genetic changes and treatment outcome. This project will use both well-established genomic profiling approaches (microarrays and sequencing) together with novel approaches - transcriptomic resequencing - with the goal of identifying all mutations that change proteins in a cancer cell. These studies offer an important opportunity to better understand the genetic basis of cancers that remain major problems in young people. Ultimately, this information will help the development of improved therapies for cancer.