Comprehensive profiling of transcriptional regulation to overcome and prevent adaptive Menin inhibitor resistance in KMT2A-rearranged and NPM1-mutated AML

• Applicant: Dr. Jan Christian Schröder
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557326522

Differentiation block is a common hallmark of acute myeloid leukemia (AML) caused by dysregulated transcriptional programs that drive leukemia development and cell survival, such as high levels of HOX/MEIS1 gene expression. Although critical epigenetic regulators such as KMT2A and transcription factors remain elusive targets, work from Prof. Scott Armstrong’s group has recently identified the cofactor Menin as a targetable gene dependency that is vital for leukemogenic gene expression in patients with KMT2A-rearranged and also NPM1-mutant AML, the most common genetic AML subtype. Initial results from early clinical trials show promising efficacy of Menin inhibitors in relapsed or refractory (R/R) KMT2A-rearranged and NPM1-mutant AML, but treatment resistance has emerged as a critical limitation, highlighting the need for synergistic combination therapies. Although the development of mutations in the MEN1 gene has been observed in ~40% of patients treated with Menin inhibitors, most patients show AML progression without MEN1 mutations. Preliminary data from S. Armstrong’s group suggest that this is mediated by a novel, recurrent epigenetic mechanism of adaptive resistance associated with suppressed HOX/MEIS1 expression and a more differentiated cellular state. The goal of this proposal is to further characterize and mechanistically target adaptive resistance to Menin inhibition. As a first objective, I will further define the underlying molecular mechanisms of adaptive cellular resistance to Menin inhibition and identify a putative network of transcription factors that may compensate for the loss of MEIS1 and other key drivers of leukemogenic gene expression under Menin inhibitor treatment. Since durable responses are unlikely to be achieved with monotherapy, my second objective is to identify drug combinations that may overcome or even prevent adaptive resistance to Menin inhibition. Building on preliminary work demonstrating the synergy of Menin inhibitors with the novel, potent Ikaros degrader mezigdomide and the KAT6A inhibitor PF-9363, I will investigate the potential of these agents in in vitro and in vivo models of adaptive resistance. If positive, these novel combination therapies can be rapidly translated into early clinical trials in patients with Menin inhibitor resistance or other related molecular vulnerabilities. This offers a high chance of discovering new treatments that will improve the poor prognosis of R/R AML patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Scott A. Armstrong, Ph.D.