Acute myeloid leukemia (AML) arises when hematopoietic stem and progenitor cells acquire mutations that rewire their gene-regulatory programs. Epigenetic plasticity is central to this transformation, yet we still know little about which chromatin factors maintain normal stem cell programs and how mutant proteins hijack them to drive leukemia. Understanding these mechanisms opens the door to therapies that act at different stages of disease, from preleukemic clones to established leukemia.

Our work focuses on AML with mutations in nucleophosmin 1 (NPM1), the most common genetic alteration in adult AML. We recently uncovered a novel epigenetic mechanism of transition to the leukemic-state, mediated by direct chromatin binding of mutant NPM1 and transcriptional regulation of a specific set of stem-cell genes together with the KMT2A (MLL1)–Menin complex. This work provided the mechanistic rationale for Menin inhibitors, which have since shown clinical activity in patients with NPM1-mutated AML. Building on this discovery and employing cutting-edge low-input chromatin technologies and in vivo and in vitro models of preleukemia, we want to address these questions:

1) How are normal hematopoietic stem cell programs regulated at the epigenetic level?

2) What epigenetic landscape alterations govern the transition to tumorigenicity?

3) How can we exploit epigenetic dependencies to pharmacologically target premalignant and malignant states?

By deconvoluting the different stages of leukemogenesis we aim to identify cancer-specific vulnerabilities and develop novel therapeutic strategies.

Gotthardt G, Weckesser J, Tascher G, Barros da Gama S, Uckelmann HJ, Sun S, Schwalm MP, Mosler T, Ferrario G, Friedmann Angeli JP, Münch C, Knapp S, Müller S. Cysteine-reactive covalent chloro-N-acetamide ligands induce ferroptosis mediated cell death. EMBO Rep. 2025.                               

Mende H, Khatri A, Lange C, Poveda-Cuevas SA, Tascher G, Covarrubias-Pinto A, Löhr F, Koschade SE, Dikic I, Münch C, Bremm A, Brunetti L, Brandts CH, Uckelmann HJ, Dötsch V, Rogov VV, Bhaskara RM, Müller S. An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant. Cell Rep, 2023. 

Uckelmann HJ, Haarer EL, Takeda R, Wong EM, Marinaccio C, Hatton C, Perner F, Antonissen N, Rajput M, Yang L, Brunetti L, Chen CW, Armstrong SA#. #Co-corresponding author. Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia. Cancer Discovery, 2023. 

Ellegast J, Alexe G, Hamze A, Lin S, Uckelmann HJ, Rauch P, Pimkin M, Ross L, Dharia N, Robichaud A, Saur Conway A, Khalid D, Perry J, Wunderlich M, Benajiba L, Pikman Y, Nabet B, Nathanael Gray, Orkin S, and Stegmaier K. Cancer Discovery, 2022.

Uckelmann HJ, Kim SM, Wong EM, Hatton C, Giovinazzo H, Gadrey JY, Krivtsov AV, Rü cker FG, Döhner K, McGeehan GM, Levine RL, Bullinger L, Vassiliou GS, Armstrong SA. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science, 2020. 

Heikamp EB, Henrich JA, Perner F, Wong EM, Hatton C, Wen Y, Barwe SP, Gopalakrishnapillai A, Xu H, Uckelmann HJ, Takao S, Kazansky Y, Pikman Y, McGeehan GM, Kolb EA, Kentsis A, Armstrong SA. The Menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. Blood, 2021.

Krivtsov AV, Evans K, Gadrey JY, Eschle BK, Hatton C, Uckelmann HJ, Ross KN, Perner F, Olsen SN, Pritchard T, McDermott L, Jones CD, Jing D, Braytee A, Chacon D, Earley E, McKeever BM, Claremon D, Gifford AJ, Lee HJ, Teicher BA, Pimanda JE, Beck D, Perry JA, Smith MA, McGeehan GM, Lock RB, Armstrong SA. A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia. Cancer Cell, 2019. 

Uckelmann HJ, Armstrong SA, Stone RM. Location, Location, Location: Mutant NPM1c Cytoplasmic Localization Is Required to Maintain Stem Cell Genes in AML. Cancer Cell, 2018.

Uckelmann H, Blaszkiewicz S, Nicolae C., Haas S., Schnell A., Wurzer S, Wagener R., Aszodi A., Essers MAG. Extracellular Matrix Protein Matrilin-4 Regulates HSC Stress Proliferation via CXCR4. J Exp Med, 2016. 

Haas S, Hansson J, Klimmeck D, Loeffler D, Velten L, Uckelmann H, Wurzer S, Prendergast AM, Schnell A, Hexel K, Santarella-Mellwig R, Blaszkiewicz S, Kuck A, Geiger H, Milsom MD, Steinmetz LM, Schroeder T, Trumpp A, Krijgsveld J, Essers MAG. Cell Stem Cell, 2015. 

Hämmerle M, Gutschner T, Uckelmann H, Ozgur S, Fiskin E, Gross M, Skawran B, Geffers R, Longerich T, Breuhahn K, Schirmacher P, Stoecklin G, Diederichs S. Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). Hepatology, 2013.

Pubmed Link: https://pubmed.ncbi.nlm.nih.gov/?term=uckelmann+h&sort=date

To apply for a PhD, medical doctorate or postdoc position, email your CV and cover letter describing your background and career objectives to: mailto:hannah.uckelmann@tum.de

• CRC 1709
• DFG
• eha
• erc
• Deutsche Krebshilfe