Targeting aberrant chromatin modifiers in clonal hematopoiesis and pre-leukemia.

• Applicant: Dr. Florian Perner
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528168324

Myeloid malignancies, including Acute Myeloid Leukemia (AML), Myeloproliferative Neoplasms (MPN) and Myelodysplastic Syndromes (MDS) are malignancies of the hematopoietic system and occur predominantly in the older population. Recent DNA-sequencing studies and lineage-tracing efforts have demonstrated that founding mutations of these diseases arise in hematopoietic stem cells early in live and undergo a lifelong process of clonal evolution. During aging of the hematopoietic system, intrinsic and environmental factors eventually lead to expansion of these clones and acquisition of additional mutational events promoting clonal evolution and disease development. The genes most frequently affected by age-related somatic variants in blood cells are coding for the DNA-methylation modifiers DNMT3A and TET2. Mutations in these enzymes lead to skewing in the distribution of methylcytosine and hydroxy-methylcytosine across the DNA and thereby impact stemness, lineage-identity and cytokine secretion by epigenetic re-programming. The exact molecular mechanisms that are critical for the cell-intrinsic competitive advantage of these mutant pre-leukemic cells remains poorly understood to date. Therefore, therapeutic interventions to prevent clonal evolution and ultimately blood cancer development have yet not been established. Data from our group indicates, that cells harboring mutations in DNMT3A and TET2 are selectively vulnerable to functional perturbation of MLL1, an evolutionary conserved histone methyltransferase. The question of how exactly somatic mutations in DNA-methylation modifiers cause this dependency on a chromatin writer will be addressed in this proposal. To date, DNA methylation and chromatin biology are largely regarded as separate epigenetic regulatory principles. Our work aims to connect these epigenetic entities in the field of clonal evolution in hematopoiesis. Aside from the expected insights into basic biological principles, this work is of potential therapeutic relevance, since small molecule inhibitors targeting oncogenic MLL1 complexes have recently been developed and tested in early-phase clinical trials. Those molecules are highly selective, well tolerated and show promise for the treatment of patients with leukemia. In this project, we will test the ability of these novel compounds to selectively impair fitness of DNMT3A and TET2 mutant hematopoietic cells and provide a proof of concept that targeting of premalignant clonal evolution is feasible. We hope that this work will be the basis for the development of therapeutic strategies that may help to prevent malignant transformation in patient at high risk in the future.

• DFG Programme: Independent Junior Research Groups