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Research interests

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  We are a junior research group interested in oncogenic signaling pathways and drug resistance, with a special focus on myeloid leukemias and the docking protein Grb2-associated binder 2 (Gab2).  
     
 
Docking proteins, like Gab2, represent hubs in tyrosine kinase signalling networks. Following their recruitment and tyrosine phosphorylation, they function as assembly platforms for specific SH2 domain-containing effectors, leading to the activation of downstream signaling pathways. Following its tyrosine phosphorylation, Gab2 recruits effector proteins such as the tyrosine phosphatase Shp2 and phosphatidylinositol (PI)3-kinase, leading to potentiation of the Ras/ERK and PI3-kinase/AKT pathways, respectively (Figure 1). As an interaction partner and effector/activator of various oncoproteins such as the RTKs of the EGFR/HER and FGFR families, Bcr-Abl or Shp2/PTPN11 mutants, Gab2 is increasingly implicated in several malignancies.
 
   
 

Figure 1: Coupling of the Gab2 docking protein to plasma-membrane associated receptors
Under physiological circumstances, growth factor activated RTKs or cytokine receptors recruit Gab2 via the small adaptor protein Grb2. Grb2 binds with its central SH2 domain to a phosphorylated tyrosine residue in the RTK leading to phosphorylation of Gab2 and recruitment of SH2-domain containing effectors such as PI3-K and Shp2.

Current projects

 
  1. The role of Gab2 and mast cells in chronic myeloid leukemia (CML) (DFG funded Project)  
 
Despite the fact that CML is a well-studied disease and that Bcr-Abl inhibitors are heralded as prototypic examples of successful targeted therapies, there are still fundamentally important questions that need to be addressed to provide safer and more sustainable therapies. We are convinced that understanding the role of the Gab2 signaling complex in CML will provide key answers to these questions. Within this project, we would like to analyze the contribution of Gab2 to the proliferation and differentiation capacity of leukemic stem cells (LSCs) and to establish Gab2 as a biomarker guiding tyrosine kinase inhibitor (TKI) treatment. With the availability of the CML mouse model (SCLtTA/TRE-BCR-ABL1) mice expressing a full or reduced dose of Gab2, or no Gab2 at all, we are now able to address these questions in a pre-clinical in vivo setting. In addition, and encouraged by our previous finding that mast cells infiltrated the bone marrow and kidney of Bcr-Abl positive mice in a Gab2 dependent manner, we would like to analyze the role of mast cells in more detail. We will answer these questions with the use of our CML mouse model, but we will also extend our analysis to samples from CML patients. Although both aims represent independent subprojects, they complement each other by addressing the role of Gab2 as an integrator and modulator of extracellular signals shaping stem cell niches and inflammatory microenvironments.
 
     
  2. The role of Gab2 in systemic mastocytosis  
 

Systemic mastocytosis is a rare disorder and characterized by infiltration of abnormal mast cells in different tissues, including bone marrow, skin, spleen, liver and the gastrointestinal tract. Independent studies in Gab2 knock-out mice revealed that Gab2 deficient mast cells had a defect in degranulation and cytokine expression. In addition, mast cell numbers were highly decreased in the stomach, peritoneum and the skin of these mice. Thus, in contrast to hematopoiesis in general, Gab2 seems to be highly important for mast cell development. Therefore, we aim to analyze the impact of Gab2 on systemic mastocytosis. We will pursue this aim by using established human mastocytosis cell lines as well as patient biopsies.

 
     
 

Sies K, Spohr C, Grunder A, Todorova R, Uhl FM, Huber J, Zeiser R, Pahl HL, Becker H, Aumann K, Brummer T, Halbach S (2019) Gab2 is Essential for Transformation by FLT3-ITD in Acute Myeloid Leukemia. Hemasphere 3 (2):e184. doi:10.1097/HS9.0000000000000184

 
 

Halbach S, Dengjel J, Brummer T (2016a) Quantitative Proteomics Analysis of Leukemia Cells. Methods Mol Biol 1465:139-148. doi:10.1007/978-1-4939-4011-0_12

 
 

Halbach S, Hu Z, Gretzmeier C, Ellermann J, Wohrle FU, Dengjel J, Brummer T (2016b) Axitinib and sorafenib are potent in tyrosine kinase inhibitor resistant chronic myeloid leukemia cells. Cell Commun Signal 14 (1):6. doi:10.1186/s12964-016-0129-y

 
 

Halbach S, Kohler M, Uhl FM, Huber J, Zeiser R, Koschmieder S, Aumann K, Brummer T (2016c) Gab2 is essential for Bcr-Abl-mediated leukemic transformation and hydronephrosis in a chronic myeloid leukemia mouse model. Leukemia 30 (9):1942-1945. doi:10.1038/leu.2016.92

 
 

Halbach S, Rigbolt KT, Wohrle FU, Diedrich B, Gretzmeier C, Brummer T, Dengjel J (2013) Alterations of Gab2 signalling complexes in imatinib and dasatinib treated chronic myeloid leukaemia cells. Cell Commun Signal 11 (1):30. doi:10.1186/1478-811X-11-30

 
 

Wohrle FU, Halbach S, Aumann K, Schwemmers S, Braun S, Auberger P, Schramek D, Penninger JM, Lassmann S, Werner M, Waller CF, Pahl HL, Zeiser R, Daly RJ, Brummer T (2013) Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors. Leukemia 27 (1):118-129. doi:10.1038/leu.2012.222

 
     
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