Identification of new cancer specific genetic and epigenetic biomarkers for cancer evolution and Minimal Residual Disease (MRD) in peripheral blood samples
General Genetics and Functional Genome Biology
Human Genetics
Final Report Abstract
Multiple Myeloma (MM) is a genetically heterogeneous disease and clonal evolution is known to play an important role in its progression. Even though a plethora of potent drugs are available and novel immunotherapies are currently being integrated into the treatment landscape, resistance remains one of the biggest clinical challenges with the underlying mechanisms largely unknown. In the course of the disease, patients frequently acquire genetic and epigenetic alterations that either transmit a fitness advantage to the tumor or a drug escape mechanism. Therefore, the quantification of cancer cells remaining after therapy (MRD) is important to predict the clinical outcome of a patient, but universal biomarkers for NGS-MRD are lacking. In this work, we have identified new drug resistance mechanisms to standard and novel therapies. Prone regions harboring (epi)genetic alterations are the drug binding site, associated genes in the network, interaction partners, or general mechanisms affecting drug tolerance e.g. efflux pumps or apoptosis receptors. Moreover, in recent years multi-omic analysis techniques have undergone huge technical advances and new insights can be gained by the integration of different regulatory levels e.g. with the Oxford Nanopore Sequencing Technology (ONT) the full genome and the full DNA methylome can be sequenced from the same sample in parallel. As MRD markers, DNA methylation marks have two big advantages in comparison to SNVs. First, tumor cells of the same type tend to exhibit similar DNA methylation changes and second the sensitivity can be increased by taking the status of several adjacent CpGs into account. Applying machine learning algorithms on a DNA methylation dataset comprising over 1,800 individuals with different hematological cancers and healthy controls, a total of 66 hypomethylated loci were identified, separating Multiple Myeloma from healthy controls and exhibiting an intermediate state in monoclonal gammopathy of undetermined significance (MGUS). These hits are suitable markers for the development of a non-invasive liquid biopsy test and the translational applicability of such a test is broad, reaching from early diagnosis to drug resistance assessment, MRD monitoring, and relapse management.
Publications
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Advanced Risk Stratification in Multiple Myeloma Beyond Traditional FISH: The First Prospective Real-World Evidence for SKY92 Gene Expression Profiling. Blood, 140(Supplement 1), 4273-4274.
Zhou, Xiang; Hofmann, Annika; Vogt, Cornelia; Nerreter, Silvia; Teufel, Eva; Stanojkovska, Emilia; Truger, Marietta; Engel, Benedict; Barcic, Anastasia; Peter, Jessica; Riedhammer, Christine; Steinhardt, Max Johannes; Xiao, Xianghui; Hornburger, Hannah; Han, Seungbin; Haertle, Larissa; Munawar, Umair; Mersi, Julia; Haferlach, Claudia ... & Kortuem, K. Martin
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All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. Haematologica, 108(2), 568-580.
García-Guerrero, Estefanía; Rodríguez-Lobato, Luis G.; Sierro-Martínez, Belén; Danhof, Sophia; Bates, Stephan; Frenz, Silke; Härtle, Larissa; Götz, Ralph; Sauer, Markus; Rasche, Leo; Kortüm, K. Martin; Pérez-Simón, Jose A.; Einsele, Hermann; Hudecek, Michael & Prommersberger, Sabrina R.
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DNA Epimutationen als neuer Resistenzmechanismus für Proteasom Inhibitoren im Multiplen Myelom. GHO (Deutsche Gesellschaft für Hämatologie und medizinische Onkologie) 2022, Vienna, Austria.
Haertle L. & Kortüm K. M.
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Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-Atpase (PSMC) Gene Family Transmit Proteasome Inhibitor Resistance in Multiple Myeloma By Impacting the ADP/ATP Binding Pocket. Blood, 140(Supplement 1), 4318-4319.
Haertle, Larissa; Cuesta, Hernandez Hipolito Nicolas; Buenache, Natalia Sofia; Simicek, Michal; Snaurova, Renata; Rapado, Inmaculada; Martinez, Nerea; López-Muñoz, Nieves; Sanchez-Pina, Jose Maria; Colmenares, Rafael; Sanchez-Beato, Margarita; Piris, Miguel Angel; Plaza, Menacho Ivan; Kemal, Samur Mehmet; Munshi, Nikhil C.; Ayala, Rosa; Kortuem, K. Martin; Barrio, Santiago & Martinez-Lopez, Joaquin
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Immune Checkpoint CD200/CD200R Decreases T Cell-Mediated Cytotoxicity Via Dok2 and Is Regulated By P53 in Multiple Myeloma. Blood, 140(Supplement 1), 7076-7077.
Shah, Pooja; Stuehmer, Thorsten; Haertle, Larissa; Bruennert, Daniela; Munawar, Umair; Leich, Ellen; Kraus, Sabrina; Hudecek, Michael; Chatterjee, Manik; Schlosser, Andreas; Kortuem, Martin; Bargou, Ralf C.; Einsele, Hermann; Berberich-Siebelt, Friederike & Steinbrunn, Torsten
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Impact of ABCB1 Promoter Methylation on PI-Resistance in Multiple Myeloma. Blood, 140(Supplement 1), 12462-12463.
Han, Seungbin; Haertle, Larissa; Besse, Lenka; Lee, Chien-Yun; Zhou, Xiang; Munawar, Umair; Besse, Andrej; Kull, Miriam; Bittrich, Max; Steinhardt, Max Johannes; Mersi, Julia; Teufel, Eva; Nerreter, Silvia; Vogt, Cornelia; Danhof, Sophia; Krönke, Jan; Weinhold, Niels; Raab, Marc S.; Haaf, Thomas ... & Kortuem, Martin
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Impaired Death Receptor Signaling Mediates Cross-Resistance to Immunotherapy in MM. Blood, 140(Supplement 1), 4226-4227.
Munawar, Umair; Zhou, Xiang; Prommersberger, Sabrina; Steinhardt, Max Johannes; Mersi, Julia; Bittrich, Max; Nerreter, Silvia; Vogt, Cornelia; Teufel, Eva; Han, Seungbin; Haertle, Larissa; Eiring, Patrick; Banholzer, Nicole; Danhof, Sophia; Fernández-Martín, Adrián; Truger, Marietta; Barrio, Santiago; Gallardo, Miguel; Valeri, Antonio ... & Kortuem, Martin
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Multiomic Analysis of CD38 Expression Levels in 209 Untreated and Daratumumab-Resistant Patients. Blood, 140(Supplement 1), 4230-4231.
Steinhardt, Max Johannes; Eiring, Patrick; Munawar, Umair; Haertle, Larissa; Han, Seungbin; Vogt, Cornelia; Nerreter, Silvia; Teufel, Eva; Mersi, Julia; Bittrich, Max; Danhof, Sophia; Truger, Marietta; Haaf, Thomas; Barrio, Santiago; Zhou, Xiang; Martínez-López, Joaquín; Haferlach, Claudia; Hudecek, Michael; Einsele, Hermann ... & Kortuem, K. Martin
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Single-Nucleotide Variants and Epimutations Induce Proteasome Inhibitor Resistance in Multiple Myeloma. Clinical Cancer Research, 29(1), 279-288.
Haertle, Larissa; Barrio, Santiago; Munawar, Umair; Han, Seungbin; Zhou, Xiang; Simicek, Michal; Vogt, Cornelia; Truger, Marietta; Fernandez, Rafael Alonso; Steinhardt, Maximilian; Weingart, Julia; Snaurova, Renata; Nerreter, Silvia; Teufel, Eva; Garitano-Trojaola, Andoni; Da, Viá Matteo; Ruiz-Heredia, Yanira; Rosenwald, Andreas; Bolli, Niccolò ... & Kortüm, K. Martin
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Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1. Biomarker Research, 11(1).
Zhou, Xiang; Han, Seungbin; Cebulla, Nadine; Haertle, Larissa; Steinhardt, Maximilian J.; Schirmer, Daniel; Runau, Eva; Flamm, Leon; Terhorst, Calvin; Jähnel, Laura; Vogt, Cornelia; Nerreter, Silvia; Teufel, Eva; Stanojkovska, Emilia; Mersi, Julia; Munawar, Umair; Schindehütte, Magnus; Blum, Robert; Reinhold, Ann-Kristin ... & Kortüm, K. Martin
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Bortezomib-induced peripheral neuropathy and single nucleotide polymorphism in PKNOX1, DGHO 2023, Hamburg, Germany
Zhou X.; Han S.; Cebulla N.; Haertle L. & Kortüm K. M.
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Demethylation of ABCB1 promoter may induce CFZ-resistance in multiple myeloma
Han S.; Hainold A. S.; Haertle L. & Kortüm K. M.
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Differential CD38 Expression on Daratumumab-Naïve vs. Resistant Multiple Myeloma – A Direct Stochastic Optical Reconstruction Microscopy (dSTORM) analysis in 53 Patients, ASH Dec 2023, San Diego, USA
Steinhardt M. J.; Haertle L. & Kortüm K. M. et al.
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Functional characterization of GPRC5D alteration and its impact on talquetamab resistance in relapsed/ refractory multiple myeloma, ASH Dec 2023, San Diego, USA
Han S.; Munawar U.; Haertle L. ... & Kortüm K. M.
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Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-ATPase (PSMC) Gene Family in the Light of Proteasome Inhibitor Resistance in Multiple Myeloma. Cancers, 15(2), 532.
Haertle, Larissa; Buenache, Natalia; Cuesta, Hernández Hipólito Nicolás; Simicek, Michal; Snaurova, Renata; Rapado, Inmaculada; Martinez, Nerea; López-Muñoz, Nieves; Sánchez-Pina, José María; Munawar, Umair; Han, Seungbin; Ruiz-Heredia, Yanira; Colmenares, Rafael; Gallardo, Miguel; Sanchez-Beato, Margarita; Piris, Miguel Angel; Samur, Mehmet Kemal; Munshi, Nikhil C.; Ayala, Rosa ... & Martínez-López, Joaquín
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High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex. Haematologica, 108(6), 1628-1639.
Zhou, Xiang; Besse, Andrej; Peter, Jessica; Steinhardt, Maximilian Johannes; Vogt, Cornelia; Nerreter, Silvia; Teufel, Eva; Stanojkovska, Emilia; Xiao, Xianghui; Hornburger, Hannah; Haertle, Larissa; Lopez, Max Mendez; Munawar, Umair; Riedel, Angela; Han, Seungbin; Maurits, Elmer; Overkleeft, Herman S.; Florea, Bogdan; Einsele, Hermann ... & Rasche, Leo
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Intracytoplasmatic BCMA Point Mutation and Teclistamab Resistance: Genomic Assessment of a Multidrug-resistant Multiple Myeloma Patient, ASH Dec 2023, San Diego, USA
Buenache Cuenda N. & Haertle L.
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P44 DETECTION OF SOLUBLE BCMA IN TEARS OF MM PATIENTS TREATED WITH BELANTAMAB MAFODOTIN. HemaSphere, 7(S2), 35–35.
Munawar, U.; Theuersbacher, J.; Haertle, L.; Zhou, X.; Han, S.; Regensburger, A.; Mersi, J.; Bittrich, M.; Seifert, F.; Haider, M.S.; Nerreter, S.; Vogt, C.; Teufel, E.; Einsele, H.; Rasche, L.; Kampik, D. & Kortüm, K.M.
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P45 HIGH-DOSE CARFILZOMIB ACHIEVES SUPERIOR ANTI-TUMOR ACTIVITY OVER LOW-DOSE AND RECAPTURES RESPONSE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA RESISTANT TO LOW-DOSE CARFILZOMIB BY CO-INHIBITING THE B2 AND B1 PROTEASOME SUBUNITS. HemaSphere, 7(S2), 35-36.
Zhou, X.; Besse, A.; Peter, J.; Steinhardt, M. J.; Vogt, C.; Nerreter, S.; Teufel, E.; Stanojkovska, E.; Xiao, X.; Hornburger, H.; Haertle, L.; Mendez, Lopez M.; Munawar, U.; Riedel, A.; Han, S.; Maurits, E.; Overkleeft, H. S.; Florea, B.; Einsele, H. ... & Rasche, L.
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P52 RISK STRATIFICATION COMBINING SKY92 GENE EXPRESSION PROFILING AND TRADITIONAL FISH IN MULTIPLE MYELOMA: THE FIRST PROSPECTIVE EVIDENCE IN THE R2-ISS ERA. HemaSphere, 7(S2), 39-39.
Zhou, X.; Hofmann, A.; Vogt, C.; Nerreter, S.; Teufel, E.; Stanojkovska, E.; Truger, M.; Engel, B.; Xiao, X.; Eisele, F.; Weis, P.; Barcic, A.; Peter, J.; Riedhammer, C.; Steinhardt, M. J.; Hornburger, H.; Han, S.; Haertle, L.; Munawar, U. ... & Rasche, L.
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Secondary genetic events impact the expression of key immunotargets on the surface of Multiple Myeloma cells, ASH Dec 2023, San Diego, USA
Munawar U.; Eiring P.; Vogt C.; Haertle L. & Kortüm K. M.
