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Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III Innovate Trial

Judith Trotman, Christian Buske, Alessandra Tedeschi, Jeffrey V Matous, David MacDonald, Constantine S Tam, Olivier Tournilhac, Shuo Ma, Steven P Treon, Albert Oriol, Jerry Ping, Eva M Briso, Israel Arango-Hisijara, Meletios A Dimopoulos
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Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström's Macroglobulinemia

Lisa Marie Kaiser, Mirja Harms, Daniel Sauter, Vijay P S Rawat, Mirco Glitscher, Eberhard Hildt, Daniel Tews, Zachary Hunter, Jan Münch, Christian Buske
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One of the goals of the consortium is to combine clinical research with translational research focussing on our understanding of the molecular and cellular biology of WM.


Areas of research cover topics such as genetics and epigenetics, the role of non-coding RNAs, the crosstalk between WM and its microenvironment, measurement of minimal residual disease (MRD). Examples for current research projects are:


Characterizing the effect of the endogenous CXCR-4 inhibitor EPX4 in Waldenstrom’s Macroglobulinemia (WM) (L. Kaiser, J. Münch, D. Sauter, C. Buske, Ulm, Germany)


This project funded by the IWMF-LLS Strategic Research Roadmap Initiative, focusses on novel endogenous anti-cancer peptides to target WM. Activating mutations of the CXCR4 gene are frequent in patients suffering from Waldenstrom´s Macroglobulinemia. Presence of mutations in both genes MYD88 and CXCR4 are accompanied by a relative insensitivity to the BTK inhibitor ibrutinib and result in an inferior treatment outcome. CXCR4 is an evolutionarily highly conserved G protein-coupled receptor that plays a pivotal role in cell adhesion and migration of lymphoma cells. Based on screening a human blood-derived peptide library, we recently identified an as-yet-unknown, naturally occurring inhibitor of CXCR4 signaling. The 16-mer peptide named EPI-X4 (Endogenous Peptide Inhibitor of CXCR4) was shown to specifically interfere in the cross-talk between CXCR4 positive hematopoietic stem cells and their environment. Our goal is to evaluate the anti-WM activity of a novel anti-CXCR4 endogenous peptide and to develop optimized derivatives as potential clinical tool in WM.



Establishing a mouse model of MYD88/CXCR4 mutated Waldenstrom’s Macroglobulinemia (L. Kaiser, H. Rahimi, C. Buske, Ulm, Germany)


To examine whether CXCR4 mutations collaborate with MYD88 L252P in inducing WM in mice, we established, in cooperation with Christian Reinhardt (University of Cologne), breeding of mice, in which cre-mediated recombination leads to the conditional expression of Myd88p.L252P mutation. Overexpression of the most common CXCR4 mutation S338X in these mice, will shed light on the role of the two mutations on lymphoma formation. Detailed histopathological and immunological analyses are used to describe disease progression and classification.