Identifikation von Resistenzmechanismen gegen die pharmakologische Hemmung der MLL-MENIN-Interaktion in der Akuten Myeloischen Leukämie.
Zusammenfassung der Projektergebnisse
Menin is a chromatin adaptor protein which is critical for the formation and stability of multiprotein complexes on chromatin, including Mixed Lineage Leukemia 1 (MLL1; KMT2A) histone methyltransferase complexes. Menin is critical for acute leukemias driven by rearrangements involving MLL1 (MLLr) or mutations of the Nucleophosmin gene (NPM1c). Small molecule inhibitors that disrupt the interaction between Menin and MLL1 have been developed and demonstrate potent activity in preclinical models. Several Menin-inhibitors recently entered phase 1 clinical trials. The Menin inhibitor SNDX-5613 is safe and effective in patients with relapsed or refractory acute leukemia. Nevertheless, development of drug resistance was observed in patients and pre-clinical model systems. In this project we aimed to identify and characterize the mechanisms of resistance towards Menin inhibitors. We discovered a non-genetic mechanism of resistance which consistently leads to acquired Menin-inhibitor resistance in cell culture systems, patient-derived xenografts and leukemia patients. Epigenetic reprogramming induced by the strong selective pressure of drug exposure led to global changes in gene expression, involving the transcription of core oncogenic effector genes. Because of this reprogramming process leukemia cells largely lost their dependency on Menin while remaining highly addicted to the MLL-rearrangement. This setting is unique in a sense that this change in cell state and functional dependency profile is not hard coded on the DNA and therefore potentially reversible. Therefore, we thought to find a molecular switch that would allow the reinstatement of a drug sensitive state to overcome resistance. Using genome-wide CRISPR-Cas9 screening we identified the histone acetyltransferase KAT6A as being such a switch. Targeting of KAT6A using either genetic tools or a highly selective small molecule inhibitor indeed allowed to restore Menin-inhibitor activity in previously resistant cells. Furthermore, we discovered, that KAT6A is binding chromatin together with Menin and MLL1 and is therefore a so far unrecognized part of the oncogenic protein complex. Follow-up mechanistic studies and pre-clinical trials in patient-derived xenografts are currently underway to fully reveal the biology and therapeutic implications of our findings. To the best of our knowledge, this is the first proof of the concept that targeted re-programming of a pathological epigenetic state is practically feasible. Our work on this project further highlights the utility of CRISPR-Cas9-based functional genomic screening of relevant model systems to reliably reveal biological vulnerabilities and allow the relatively rapid translation of findings to clinical innovation.
Projektbezogene Publikationen (Auswahl)
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YBX1 mediates translation of oncogenic transcripts to control cell competition in AML. Leukemia, 36(2), 426-437.
Perner, Florian; Schnoeder, Tina M.; Xiong, Yijun; Jayavelu, Ashok Kumar; Mashamba, Nomusa; Santamaria, Nuria Tubio; Huber, Nicolas; Todorova, Kristina; Hatton, Charles; Perner, Birgit; Eifert, Theresa; Murphy, Ciara; Hartmann, Maximilian; Hoell, Jessica I.; Schröder, Nicolas; Brandt, Sabine; Hochhaus, Andreas; Mertens, Peter R.; Mann, Matthias ... & Heidel, Florian H.
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A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition. Cancer Discovery, 13(1), 146-169.
Soto-Feliciano, Yadira M.; Sánchez-Rivera, Francisco J.; Perner, Florian; Barrows, Douglas W.; Kastenhuber, Edward R.; Ho, Yu-Jui; Carroll, Thomas; Xiong, Yijun; Anand, Disha; Soshnev, Alexey A.; Gates, Leah; Beytagh, Mary Clare; Cheon, David; Gu, Shengqing; Liu, X. Shirley; Krivtsov, Andrei V.; Meneses, Maximiliano; de Stanchina, Elisa; Stone, Richard M. ... & Allis, C. David
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IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia. Nature Cancer, 3(5), 595-613.
Aubrey, Brandon J.; Cutler, Jevon A.; Bourgeois, Wallace; Donovan, Katherine A.; Gu, Shengqing; Hatton, Charlie; Perlee, Sarah; Perner, Florian; Rahnamoun, Homa; Theall, Alexandra C. P.; Henrich, Jill A.; Zhu, Qian; Nowak, Radosław P.; Kim, Young Joon; Parvin, Salma; Cremer, Anjali; Olsen, Sarah Naomi; Eleuteri, Nicholas A.; Pikman, Yana ... & Armstrong, Scott A.
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The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. Blood, 139(6), 894-906.
Heikamp, Emily B.; Henrich, Jill A.; Perner, Florian; Wong, Eric M.; Hatton, Charles; Wen, Yanhe; Barwe, Sonali P.; Gopalakrishnapillai, Anilkumar; Xu, Haiming; Uckelmann, Hannah J.; Takao, Sumiko; Kazansky, Yaniv; Pikman, Yana; McGeehan, Gerard M.; Kolb, Edward A.; Kentsis, Alex & Armstrong, Scott A.
