Transdifferentiation of malignant B-cells

• Applicant: Dr. Heiko Bruns
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 356872912

Tumor-infiltrating macrophages often constitute a significant part of infiltrating immune cells. In B-cell lymphomas, the presence of tumor-associated-macrophages (TAMs) has been reported to be associated with poor prognosis. Interestingly it was shown, that mature B-cells could be efficiently re-programmed into macrophages by the overexpression of myeloid-specific transcription factors. Moreover, other studies observed in vitro that this lymphoid/myeloid plasticity might be also caused by oncogenes in cultured B-cells of murine lymphoma models. Therefore we consider, if lymphoma B-cells themselves might be a source of TAMs, besides the well-known infiltration of monocytic cells into the tumor environment. Based on the system of CD45.1/2 allotypes, a murine model of lymphoma was developed, which allows tracking of the conversion of lymphoma B-cells into TAMs. It could be shown, that some lymphoma B-cells of the established model in fact spontaneously switched into a macrophage-like phenotype. Accordingly, they start to express typical macrophage markers, but seem to perform a transition into a myeloid-like expression profile on the level of transcription as well. Furthermore, analysis of the recombined immunoglobulin heavy chain confirmed the clonal identity of lymphoma b-cells and TAMs. Which consequences the lymphoid/myeloid plasticity of lymphoma B-cells has for tumor development, progression, as well as for the outcome of therapy, is unknown. Based on these initial results, we now want to dissect the functional contribution of transdifferentiation to disease relapse and therapy resistance. In our DFG proposal, we specifically aim to (i) perform global RNA-Seq analysis of transdifferentiated macrophages, (ii) analyze the effect of chemotherapy on transdifferentiated macrophages and (iii) establish a mouse model with which we can investigate whether transdifferentiated macrophages can oscillate between B-lymphoid and myeloid lineages especially after chemotherapy.The new insights gained from this project will discover whether the transdifferentiation-process is an immune/therapy escape mechanism of lymphoma cells, and to form the basis for advanced studies and new intervention strategies to prevent the transdifferentiation-process in high grade lymphomas.

• DFG Programme: Research Grants