B11 (New): Novel oncogenes in complex karyotype acute myeloid leukemia

Complex karyotype (ck) AML represent about 10-20% of all AML, increase with older age. and are associated with poor outcome. ckAML frequently involve loss of chromosomes 5q, 7q and 17p. We provide preliminary data suggesting that loss of chromosomal material does not only lead to loss of candidate tumor suppressor activity, but also to the activation of novel proto-oncogenes. We identified ckAML cases carrying a chromosome 7q deletion [del(7q)] that leads to activation of MNX1, a homeobox transcription factor. MNX1 becomes activated through an enhancer hijacking event translocating an enhancer from one breakpoint region into the vicinity and putative transcriptional activation domain of MNX1. To address our hypothesis, we will 1) focus on ckAML with del(7q); cases will be identified using EPIC methylation arrays from ckAMLs which provide the information on copy number variation as well as DNA methylation which will be used as a marker for epigenetic alterations; 2) perform whole genome sequencing, ChIP-seq (e.g., H3K27ac, H3K4 me1) and Hi-C of ckAML with del(7q) and will identify the chromosomal breakpoints and putative enhancer hijacking events; 3) characterize the novel oncogenes for their leukemic potential which may require an additional leukemic hit in form of haploinsufficiency of suppressor genes located in the deleted region. These studies may lead to the identification of novel oncogenes and therapeutic targets for AML.

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