The AACR Gertrude B. Elion Cancer Research Award is open to tenure-track scientists at the level of assistant professor, who completed postdoctoral studies or clinical research fellowships no more than four years prior to the start of the grant term.
Charles G. Mullighan, M.D.
Assistant Member, St. Jude Children's Research Hospital, Memphis, TN
Exome Sequencing of Hypodiploid Acute Lymphoblastic Leukemia
"The goal of this project is to comprehensively sequence the coding genome of cases of hypodiploid acute lymphoblastic leukemia (ALL), in order to identify the genetic basis of this high risk disease. ALL is the commonest childhood cancer, and despite therapeutic advances remains the leading cause of cancer-related death in children and young adults. Recurring chromosomal alterations are a hallmark of childhood ALL, and include aneuploidy and chromosomal translocations. Hypodiploidy, in which multiple chromosomes have been lost by the tumor cells, is associated with particularly poor prognosis, but the genetic basis of aneuploidy and poor outcome is poorly understood. My previous work has performed integrated genomic profiling of a large cohort of hypodiploid ALL cases using SNP and gene expression microarrays and candidate gene sequencing. This work has shown that different subtypes of hypodiploid ALL harbor distinct genomic alterations, including a high frequency of activating Ras pathway mutations and alterations of IKZF3 (encoding the transcription factor AIOLOS) in cases with near haploid (24-31 chromosomes) karyotypes, and alterations of IKZF2 (encoding HELIOS) in low hypodiploid (32-39 chromosomes) cases. However, a substantial proportion of cases lack alterations in these genes, and the genetic basis of aneuploidy remains poorly understood. Sequencing of the coding genome (“exome” sequencing) is a convenient way to identify DNA sequence alterations in tumor genomes. In a pilot experiment, we performed liquid phase capture of tumor and normal DNA of a near haploid hypodiploid ALL case followed by next-generation sequencing using the Illumina GAIIx platform. This identified 7 missense variants including novel mutations in the Ras pathway and a centrosomal regulator. Here we will sequence the tumor and normal genomes of both near haploid and low hypodiploid ALL cases using exome capture and next-generation sequencing. The frequency of mutations in novel targets of mutation will be assessed by Sanger sequencing of a panel of over 120 hypodiploid ALL cases, xenografts and cell lines. We will then correlate findings with clinical features, outcome and Ras pathway activation as assessed by intracellular phosphosignaling analysis in primary leukemia cells. Together, these approaches represent an important opportunity to dissect the genetic basis of a very high risk childhood cancer, and to identify targets and pathways for therapeutic intervention. The AACR Gertrude B. Elion Award will provide invaluable support for these novel genomic studies."
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