Studying inborn errors of immunity affecting neutrophil granulocytes DE
We identified a novel germline mutation in S100A8 causing severe congenital neutropenia (SCN) that progressed to MDS/AML. Our preliminary data indicate that the variant allele lowers endogenous S100A8/A9 protein levels. We aim at characterizing this potential novel genetic disease by applying our iPSC-derived neutrophil differentiation and bone marrow organoid systems. Specifically, we perform a proteome-based analysis of distinct developmental stages of control and S100A8-mutated iPSC-derived neutrophils. We study the impact of the identified variant on S100A8/S100A9 complex formation and neutrophil functions. We investigate if S100A8-mutant neutrophils influence the bone marrow niche and contribute to pre-leukemic changes using our iPSC-derived BMO system and single-cell multi-omics. Finally, we explore targeted strategies to prevent neutrophil-driven pre-leukemic transformation and design novel generalizable therapeutic strategies.
Team
Publications
The Rise of Bone Marrow Organoids as Next-Generation Models for Blood Formation and FailureStolz, A.; Harmon, L. M.; Li, J.; Rettkowski, J.; Rodriguez-Meira, A.; Shiroshita, K.; Tran, V. L.; Khan, A.; Klein, C.
2026 Exp Hematol
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Mutations in VPS18 Lead to a Neutrophil Maturation Defect Associated with Disturbed Vesicle HomeostasisGao, J.; Bader, A.; Linder, M. I.; Cheng, J.; Richter, M.; Da Costa, R.; Zehrer, A.; Mitt, K.; Popper, B.; Meissner, F.; Wei, X.; De Vega Gómez, E.; Tatematsu, M.; Rohlfs, M.; Frenz-Wiessner, S.; Kiziltug, M.; Somekh, I.; Yacobovich, J.; Steinberg-Shemer, O.; Somech, R.; Soehnlein, O.; Schmid, B.; Klein, C.; Walzog, B.; Maier-Begandt, D.
2026 Cell Death Dis
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Gasdermin D drives focal Crystalline Thrombotic Microangiopathy by accelerating Immunothrombosis and NecroinflammationWatanabe-Kusunoki, K.; Li, C.; Bandeira Honda, T. S.; Zhao, D.; Kusunoki, Y.; Ku, J.; Long, H.; Klaus, M.; Han, C.; Braun, A.; Mammadova-Bach, E.; Linkermann, A.; Van Avondt, K.; Richter, M.; Soehnlein, O.; Linder, M. I.; Klein, C.; Steiger, S.; Anders, H.-J.
2024 Blood
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Generation of Complex Bone Marrow Organoids from Human Induced Pluripotent Stem Cells.Frenz-Wiessner, S.; Fairley, S. D.; Buser, M.; Goek, I.; Salewskij, K.; Jonsson, G.; Illig, D.; zu Putlitz, B.; Petersheim, D.; Li, Y.; Chen, P.-H.; Kalauz, M.; Conca, R.; Sterr, M.; Geuder, J.; Mizoguchi, Y.; Megens, R. T. A.; Linder, M. I.; Kotlarz, D.; Rudelius, M.; Penninger, J. M.; Marr, C.; Klein, C.
2024 Nat Methods
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Neutrophils - Biology and DiversityMaier-Begandt, D.; Alonso-Gonzalez, N.; Klotz, L.; Erpenbeck, L.; Jablonska, J.; Immler, R.; Hasenberg, A.; Mueller, T. T.; Herrero-Cervera, A.; Aranda-Pardos, I.; Flora, K.; Zarbock, A.; Brandau, S.; Schulz, C.; Soehnlein, O.; Steiger, S.; the TRR332 consortium.
2023 Nephrol Dial Transplant
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Analyzing Mitochondrial Respiration of Human Induced Pluripotent Stem Cell-Derived Myeloid Progenitors Using Seahorse TechnologyFan, Y.; Mizoguchi, Y.; Tatematsu, M.; Linder, M. I.; Frenz, S.; Choi, J.; Klein, C.
2023 STAR Protoc
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Human Genetic Defects in SRP19 and SRPRA Cause Severe Congenital Neutropenia with Distinctive Proteome ChangesLinder, M. I.; Mizoguchi, Y.; Hesse, S.; Csaba, G.; Tatematsu, M.; Łyszkiewicz, M.; Zietara, N.; Jeske, T.; Hastreiter, M.; Rohlfs, M.; Liu, Y.; Grabowski, P.; Ahomaa, K.; Maier-Begandt, D.; Schwestka, M.; Pazhakh, V.; Isiaku, A.; Briones Miranda, B.; Blombery, P.; Saito, M. K.; Rusha, E.; Alizadeh, Z.; Pourpak, Z.; Kobayashi, M.; Rezaei, N.; Unal, E.; Hauck, F.; Drukker, M.; Walzog, B.; Rappsilber, J.; Zimmer, R.; Lieschke, G. J.; Klein, C.
2023 Blood
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