Introduction: We study the mechanisms of defective gene regulation in acute myeloid leukemia (AML), with a specific focus on a unique subtype for which currently no cure is available. This subtype carries chromosomal abnormalities involving chr:3q26 causing overexpression of a gene called EVI1 (also designated MECOM). In “The New Yorker”, Tatiana Schlossberg, the granddaughter of JFK wrote a heartbreaking article about her fight against this currently incurable form of leukemia. She died on December 30^th (https://archive.ph/eUmQV). Due to this  tragic story, 3q26 rearranged leukemia received worldwide attention. This story illustrates the severity of this type of cancer and that, even though progress has been made in cancer treatment in the past decennia, there are still subtypes of cancer that are incurable. In my group we decided to focus our research on understanding the biology of this subtype of leukemia and hope to find leads to cure this dreadful disease. 

Enhancer targeting: The overexpression of the EVI1 gene, which is located at chr:3q26, is caused by so called enhancer hijacking as the result of the chromosomal rearrangements. More than ten types of 3q26 rearrangements, hijacking the same numbers of enhancers from distinct “donor-genes” have been discovered that activate EVI1 expression in AML cells in various patients. The question that we address is: Can we inhibit EVI1 expression by interfering with the enhancer activity? We identified a number of compounds, among which drugs that specifically target so called CBP/p300 proteins. Those proteins are enzymes that bind to enhancers but their activity appears to be different when bound to distinct enhancers.  To our surprise were the effects of the p300/CBP inhibitors particularly strong and showed a certain level of selectivity for the hijacked enhancers. Consequently we demonstrated that  those drugs inhibit oncogene EVI1 expression and consequently interfere with leukaemia growth in vitro. An in vivo study, investigating the effects of those drugs on leukemic outgrowth, is currently being conducted. Together with the group of Bas van Steensel we are now planning experiments to understand why certain enhancers are hijacked so frequently, what they have in common at the nucleotide level and which protein complexes are predicted to be involved in this action. We anticipate on the discovery of more specific targets. 

Targeting EVI1 function: Another approach to interfere with oncogenes, is to target their function or activity. Therefore, targeting EVI1 protein in AMLs with aberrant expression may be another way to find cures for the disease. We found that EVI1 interacts with a nuclear protein called CTBP. This interaction was found to be essential for leukemic transformation. In fact we found an experimental approach to break EVI1/CTBP interaction and demonstrated inhibition of  tumor growth in a humanized mouse model. These findings hava been published in 2024 in  ScienceAdvances. We uncovered and published a month ago what the target gene is for EVI1/CTBP. The EVI1/CTBP repressor complex binds to regulatory elements of the gene for CEBPalpha (CEBPA). CEBPA is essential for the development of healthy neutrophils. When CEBPA is mutated, absent or repressed  neutrophils cannot be generated and the chances of leukemia development  are high. Our findings that CEBPA expression is blocked by EVI1/CTBP have been published in Blood in December 2025. In collaboration with Sebastian Pomplun, we are developing now small peptide-compounds to inhibit leukemic growth in patients with a chr.3q26 rearrangement. More importantly, this work, that we carried out with Oncode support has now been used to apply for external funds. I am proud to announce that this work is now in part funded by the World Wide Cancer Foundation.  

We have now developed more models to test the effects of compounds on either the expression of EVI1 or the function by EVI1 in leukemia.  

Finally, our program has now also affected another malignancy. We have found that  EVI1 overexpression due to genetic defects occurs with high frequency in Ovarian Cancer. A manuscript is now under review.