Multiple Myeloma (MM) is the hematological malignancy with the highest number of FDA-approved drugs in recent years. Despite significant advances in treatment, primary and acquired drug resistance remain major clinical challenges. Genetic and epigenetic alterations contribute to tumor-intrinsic drug resistance and disease progression. While genetic mutations and structural variations have been extensively studied, far less is understood about the impact of epigenetic modifications, such as DNA methylation changes on aberrant transcription and protein expression. Across several drug classes, our research has identified DNA hypermethylation in key drug target genes as frequent resistance mechanisms, occurring more commonly than genetic mutations. In the context of innovative immunotherapies, we explore how (epi)genetic alterations enable MM cells to evade treatment, leading to relapse and therapy failure. By identifying resistance biomarkers, we aim to guide personalized treatment strategies, predict patient responses, and improve therapeutic outcomes. Additionally, we are investigating demethylating agents as a potential solution to overcome epigenetic drug resistance. Furthermore, we have discovered MM-specific DNA methylation biomarkers for liquid biopsy applications and are developing a minimally invasive, comprehensive diagnostic tool to track MM progression and detect minimal residual disease and emerging resistant clones by leveraging advanced sequencing technologies.

• Haertle L*, Munawar U*, Cuesta Hernández HN, Arroyo-Barea A, Heckel T, Cuenca I, Martin L, Höschle C, Müller N, Vogt C, Bischler T, Lazaro del Campo P, Han S, Buenache N, Zhou X, Bassermann F, Waldschmidt J, Steinbrunn T, Rasche L, Stühmer T, Martinez-Lopez J, Kortüm KM*, Barrio S*. Clonal Competition Assays Identify Fitness Signatures in Cancer Progression and Resistance in Multiple Myeloma. Hemasphere. 2024 Jul 11;8(7):e110. doi: 10.1002/hem3.110. eCollection 2024 Jul.
• Munawar U, Zhou X, Prommersberger S, Nerreter S, Vogt C, Steinhardt MJ, Truger M, Mersi J, Teufel E, Han S, Haertle L, Banholzer N, Eiring P, Danhof S, Navarro-Aguadero M, Fernandez-Martin A, Ortiz-Ruiz A, Barrio S, Gallardo M, Valeri A, Castellano E, Raab P, Rudert M, Haferlach C, Sauer M, Hudecek M, Martinez-Lopez J, Waldschmidt J, Einsele H, Rasche L, Kortüm KM. Impaired FADD/BID Signaling Mediates Cross-Resistance to Immunotherapy in Multiple Myeloma. Commun Biol. 2023 Dec 21;6(1):1299. doi: 10.1038/s42003-023-05683-4.
• García-Guerrero E, Rodríguez-Labato LG, Sierro-Martínez B, Danhof S, Bates S, Frenz S, Haertle L, Götz R, Sauer M, Rasche L, Kortüm KM, Pérez-Simón JA, Einsele H, Hudecek M, Prommersberger S. ATRA Works Synergistically with the y-Secretase Inhibitor Crenigacestat to Augment BCMA on Multiple Myeloma and the Efficacy of BCMA-CAR T-cells. Haematologica. 2023 Feb 1;108(2):568-580. doi: 10.3324/haematol.2022.281339.
• Zhou X*, Besse A*, Peter J, Steinhardt MJ, 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 HS, Florea B, Einsele H, Kortüm KM, Driessen C, Besse L*, Rasche L*. 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 β2 and β1 Subunits of Proteasome Complex. Haematologica. 2023 Jun 1; (6):1628-1629. doi: 10.3324/haematol.2022.282225.
• Haertle L, Buenache N, Cuesta Hernández HN, Simicek M, Snaurova R, Rapado I, Martinez N, López-Muñoz N, Sánchez-Pina JM, Munawar U, Han S, Ruiz-Heredia Y, Colmenares R, Gallardo M, Sanchez-Beato M, Angel Piris M, Kemal Samur M, Munshi NC, Ayala R, Kortüm KM, Barrio S*, Martínez López J*. 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 (Basel). 2023 Jan 15;15(2):532. doi: 10.3390/cancers15020532.
• Haertle L, Barrio S,Munawar U, Han S, Zhou X, Simicek M, Vogt C, Truger M, Alonso Fernandez R, Steinhardt M, Weingart J, Snaurova R, Nerreter S, Teufel E, Garitano-Trojaola A, Da Viá M, Ruiz-Heredia Yanira, Rosenwald A, Bolli N, Hajek R, Raab P, Raab MS, Weinhold N, Haferlach C, Haaf T, Martinez-Lopez J, Einsele H, Rasche L, Kortüm KM. Single Nucleotide Variants and Epimutations in Proteasome Inhibitor Resistance in Multiple Myeloma. Clin Cancer Res. 2023 Jan 4;29(1):279-288. doi: 10.1158/1078-0432.CCR-22-1161.
• Haertle L*, Barrio S*, Munawar U, Han S, Zhou X, Vogt C, Alonso-Fernández R, Bittrich M, Ruiz-Heredia Y, Da-Via M, Zovko J, Garitano-Trojaola A, Bolli N, Ruckdeschel A, Stühmer T, Chatterjee M, Kull M, Krönke J, Agirre X, Martin-Subero I, Raab P, Einsele H, Rasche L, Martinez-Lopez J, Haaf T, Kortüm KM. *equal contribution Cereblon Enhancer Methylation and IMiD Resistance in Multiple Myeloma. Blood. 2021 Nov 4;138(18):1721-1726. doi: 10.1182/blood.2020010452
• Truger M, Duell J, Zhou X, Heimeshoff L, Ruckdeschel A, John M, Riedel A, Hüper S, Peter J, Walter W, Haertle L, Meggendorfer M, Topp MS, Rosenwald A, Da-Via M, Bolli N, Weinhold N, Einsele H, Haferlach C, Kortüm KM*, Rasche L* Single and Double Hit Events in Genes Encoding for Immune Targets Before and After T Cell Engaging Antibody Therapy in MM. Blood Adv. 2021 Sep 1;bloodadvances.2021004418. doi: .1182/bloodadvances.2021004418.
• Munawar U, Rasche L, Müller N, Vogt C, Da Viá M, Haertle L, Arampatzi P, Dietrich S, Roth M, Garitano-Trojaola A, Steinhardt MJ, Strifler S, Gallardo M, Martinez-Lopez J, Bargou R, Heckel T, Einsele H, Stühmer T, Kortüm KM*, Barrio S*. Hierarchy of Mono- and Bi-Allelic TP53 Alterations in Multiple Myeloma Cell Fitness. Blood. 2019 Sep 5;134(10):836-840. doi: 10.1182/blood.2019000080.
• Barrio S, Munawar U, Zhu Y, Giesen N, Shi CX, Da Viá M, Sanchez R, Bruins L, Demler T, Müller N, Haertle L, Garitano-Trojaola A, Steinbrunn T, Danhof S, Cuenca I, Barrio-Garcia C, Braggio E, Rosenwald A, Martinez-Lopez J, Rasche L, Raab M, Steward K, Einsele H, Stühmer T, Kortüm KM. IKZF1/3 and CRL4-CRBN E3 Ubiquitin Ligase Mutations and IMiD Resistance in Multiple Myeloma. Haematologica. 2019 Sep 26. pii: haematol.2019.217943. doi: 0.3324/haematol.2019.217943.

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Written applications including CV are welcome and should be forwarded by email to Dr. Larissa Haertle.