The role of Gab2 in leukemia stem cells and mast cells in the context of chronic myeloid leukemia.

• Applicant: Dr. Sebastian Halbach
• Subject Area: Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455359397

The advent of tyrosine kinase inhibitors (TKIs), which block Bcr-Abl oncoprotein activity, led to a paradigm shift in tumor therapy and transformed chronic myeloid leukemia (CML) into a manageable disease for most patients. While this therapy induces long-term remission in only a minority of patients due to the persistence of leukemic stem cells (LSCs) or the development of a resistance against the given TKI, so-called “operational cures” have been observed in a fraction of patients even after discontinuation of TKI therapy. In this selected group of patients, which have attained deep molecular remission for at least three years, continued remissions were seen in approximately 40% of these patients after TKI cessation. This suggests that TKIs have led to an exhaustion of the LSC pool and that it is possible to achieve cures in a subset of patients by long-term TKI treatment. A major current challenge, however, is the identification of biomarkers that will on the one hand predict whether a patient will stay in remission or develop a TKI resistance and on the other hand inform the physicians when and whether it is safe to stop TKI administration in an individual patient. The elucidation of such predictive factors will require the identification of survival signals that act in and/or on Bcr-Abl positive stem cells and which protect LSCs against TKIs. A broader knowledge of these signals will also help to discover new targets to improve the current therapy, especially in cases of TKI resistance.Based on a large body of work identifying Gab2 as a critical signal amplifier of Bcr-Abl, tyrosine kinases and cytokine receptors, we propose that this docking protein could represent such a biomarker and integration point of microenvironmental and Bcr-Abl derived signals. Supported by our previous work demonstrating that Gab2 signaling compromises the efficacy of TKIs in tissue culture, we further postulate that its expression level represents a critical determinant for therapeutic responses. Furthermore, we could show that Gab2 deficiency impairs disease development in a chronic-phase CML mouse model. Within this application, we would like to elucidate the potential of Gab2 as a biomarker as well as a potential new drug target in CML therapy. In addition and strongly motivated by our observation that mast cells infiltrated the bone marrow of Bcr-Abl expressing mice, we will analyze the role of mast cells and their dependency on Gab2 in CML. Interestingly, we could show that Bcr-Abl expressing Gab2 deficient mice did not show any mast cell infiltration in the bone marrow, suggesting that mast cells could play a role in the development or maintenance of CML. Given the emerging role of aberrant Gab2 signaling in various hematological and solid tumor entities, we expect that this project will be of broader relevance for the field of hematology and oncology.

• DFG Programme: Research Grants