Our group investigates the cellular and molecular mechanisms driving the initiation and progression of myeloproliferative neoplasms (MPN), with a focus on how dysregulated thrombopoietin/MPL signaling in malignant hematopoietic stem and progenitor cells initiates disease. We aim to understand how these primary signaling abnormalities drive interactions between malignant and healthy hematopoietic cells, influence stromal components, remodel the bone marrow niche during disease progression, and contribute to overall disease development. Using global transcriptome and proteome profiling, spatial transcriptomics, single-cell RNA sequencing, and CRISPR-based functional screens, we map the spatial, transcriptional, and signaling dynamics of the bone marrow across different disease stages. Functional validation through in vitro and in vivo CRISPR/Cas9 genome editing enables us to determine the causal roles of specific signaling pathways and molecular drivers. Collectively, our work seeks to uncover the fundamental drivers of disease progression and identify actionable targets for therapeutic intervention.
Projects
This project focuses on defining the molecular signaling networks that initiate and sustain the malignant phenotype in MPN stem and progenitor cells. We combine global transcriptomics, phosphoproteomics, and CRISPR-based functional screens to identify key signaling pathways and regulators. Candidate drivers will be functionally validated using in vitro and in vivo CRISPR/Cas9 genome editing to determine their causal roles in disease progression and their potential as therapeutic targets.
This project investigates how malignant hematopoietic cells remodel the bone marrow microenvironment and influence healthy hematopoietic and stromal cells during disease progression. Using chimeric mouse models, spatial and single-cell transcriptomics, and multiplex cytokine profiling, we will map the dynamic changes in cell composition, spatial organization, and signaling within the BM niche. These studies aim to identify niche components and cytokine-mediated interactions that support malignant expansion and drive disease progression, providing insights into novel microenvironment-targeted therapies.
Publications
- Kauppi M, Hyland CD, Viney EM, White CA, de Graaf CA, Welch AME, Yousef J, Dagley LF, Emery-Corbin SJ, Kueh AJ, Herold MJ, Hilton DJ, Babon JJ, Nicola NA, Behrens K*, Alexander WS*. (2025) Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice. Blood 145(10): 1034-1046. * Co-senior authors
- Behrens K#, Kauppi M, Viney EM, Kueh AJ, Hyland CD, Willson TA, Salleh L, de Graaf AC, Babon JJ, Herold MJ, Nicola NA, Alexander WS. (2024) Differential in vivo roles of Mpl cytoplasmatic tyrosine residues in murine hematopoiesis and myeloproliferative disease. Leukemia 38(6): 1342-52. # Corresponding author
- Sarson-Lawrence KTG, Hardy JM, Iaria J, Stockwell D, Behrens K, Saiyed T, Tan C, Jebeli L., Scott NE, Dite TA, Nicola NA, Leis AP, Babon JJ, Kershaw NJ. (2024) Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin. Nature Communications 15(1): 1135.
- Behrens K, Brajanovski N, Xu Z, Viney EM, diRago L, Hediyeh-Zadeh S, Davis MJ, Pearson RB, Sanij E, Alexander WS, Ng AP. (2024) ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B-cell acute lymphoblastic leukaemia. Science Advances 10(10): 1126.
- Deng Y, Diepstraten ST, Potts MA, Ginger G, Trezise S, Ng AP, Healey G, Kane SR, Cooray A, Behrens K, Heidersbach A, Kueh AJ, Pal M, Wilcox S, Tai L, Alexander WS, Visvader JE, Nutt SL, Strasser A, Haley B, Zhao Q, Kelly GL, Herold MJ. (2022) Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance. Nature Communications 13(1), 4739.
- Ng AP, Coughlan HD, Hediyeh-zadeh S, Behrens K,Johanson TM,Low MSY, Bell CC, Gilan O, Chan YC, Kueh AJ, Boudier T, Feltham R, Gabrielyan A, DiRago L, Hyland CD, Ierino H, Mifsud S, Viney E, Willson T, Dawson MA, Allan RS, Herold MJ, Rogers K, Tralinton DM, Smyth GK, Davis MJ, Nutt SL, Alexander WS. (2020) An Erg-driven transcriptional program controls B cell lymphopoiesis. Nature Communications 11(11): 3013.
- Behrens K and Alexander WS. (2018) Cytokine control of megakaryopoiesis. Growth Factors 36(3-4):89-103.
- Behrens K, Maul K, Tekin N, Kriebitzsch N, Indenbirken D, Prassolov V, Mueller U, Serve H, Cammenga J, Stocking C. (2017) RUNX1 cooperates with FLT3-ITD to induce leukemia. J Exp Med 214(3): 737-52.
- Behrens K, Triviai I, Schwieger M, Tekin N, Alawi M, Spohn M, Indenbirken D, Ziegler M, Müller U, Alexander WS, Stocking C. (2016) Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions. Blood 127(26): 3369-81.
- Chien W, Sun QY, Ding LW, Mayakonda A, Takao S, Liu L, Lim SL, Tan KT, Garg M, De Sousa Maria Varela A, Xiao J, Jacob N, Behrens K, Stocking C, Lill M, Madan V, Hattori N, Sigal G, Ogawa S, Wakita S, Ikezoe T, Shih LY, Alpermann T, Haferlach T, Yang H, Koeffler HP. (2016) Diagnosis and relapse: Cytogenetically normal acute myelogenous leukemia without FLT3-ITD or MLL-PTD. Leukemia 31(3): 762-66.
- Kuvardina ON, Herglotz J, Kolodziej S, Kohrs N, Herkt S, Wojcik B, Oellerich T, Corso J, Behrens K, Kumar A, Hussong H, Urlaub H, Koch J, Serve H, Bonig H, Stocking C, Rieger MA, Lausen J. (2015) RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation. Blood 125(23): 3570-9.
- Skokowa J, Steinemann D, Katsman-Kuipers JE, Zeidler C, Klimenkova O, Klimiankou M, Unalan M, Kandabarau S, Makaryan V, Beekman R, Behrens K, Stocking C, Obenauer J, Schnittger S, Kohlmann A, Valkhof MG, Hoogenboezem R, Göhring G, Reinhardt D, Schlegelberger B, Stanulla M, Vandenberghe P, Donadieu J, Zwaan CM, Touw IP, van den Heuvel-Eibrink MM, Dale DC, Welte K. (2014) Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123(14): 2229-37.
- Niebuhr B, Kriebitzsch N, Fischer M, Behrens K, Günther T, Alawi M, Bergholz U, Müller U, Roscher S, Ziegler M, Buchholz F, Grundhoff A, Stocking C. (2013) Runx1 is essential at two stages of early murine B-cell development. Blood 122(3): 413-23
- Ross K, Sedello AK, Todd GP, Paszkowski-Rogacz M, Bird AW, Ding L, Grinenko T, Behrens K, Hubner N, Mann M, Waskow C, Stocking C, Buchholz F. (2012) Polycomb group ring finger 1 cooperates with Runx1 in regulating differentiation and self-renewal of hematopoietic cells. Blood 119(18): 4152-61.