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Research Project

Functional Studies in AML

Systematic functional interrogation of conserved interaction partners of MLL fusion proteins. (A) AP-MS-derived protein-protein interaction network of 7 selected MLL fusion proteins (schematic fusion proteins). Shown are top 300 interactors per fusion protein (based on p-values, grey and cyan circles). Cyan circles represent 128 proteins that interact with ≥5 of 7 MLL fusion proteins.

Comprehensive Functional Studies on Translocation Products in AML

Chromosomal translocations are frequent events in leukemia. Often, this event fuses two genes, thereby creating novel proteins with oncogenic functions. In many cases, the molecular mechanism of cellular transformation of these translocation products is unknown. We have already established a number of cancer cell lines with inducible expression of affinity tagged variants of translocation products for  a comprehensive analysis of their oncogenic activities.

Critical Effectors of NUP98 Fusions in AML

Comparative analysis of four selected NUP98-fusion proteins using a mouse bone marrow transplantation model: Bioluminescence imaging of secondary recipient mice transplanted with primary NUP98-FP AML cells in the absence or presence of Dox.

A significant number of genes is involved in a series of cytogenetically distinct translocation events involving more than one fusion partner gene, resulting in “Multi-Partner Translocation (MPT) families”. MPT families share the biochemical properties of one common partner moiety, but at the same time feature very different functions of the unique fusion partner gene parts. An important MPT family in AML comprises fusions involving the NUP98 (Nucleoporin 98) gene, featuring >20 different fusion proteins.

Lung Cancer

Lung cancer is leading the worldwide cancer related deaths. It can be divided into to two main types: Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC), the later accounting for 80% of the cases. Common genetic alterations associated with lung cancer are the loss of tumor suppressors, like p53, LKB1 etc. and activating mutations, overexpression, amplification of oncogenes, such EGFR and K-RAS. In lung tumors, EGFR signals through K-RAS, PI3K and STAT3.

C/EBPa mutations in AML

C/EBPa mutations in AML

Nine percent of patients with Acute Myeloid leukemia (AML) have mutations in the gene encoding the transcription factor CCAAT-enhancer-binding protein alpha (C/EBPa, CEBPA). Although it is known that these mutations induce a block in myeloid differentiation and lead to increased self renewal, the molecular mechanisms underlying these changes are still poorly understood. In the recent past, we have established a number of cell line models that allow functional studies of CEBPA mutations. We are now employing shRNA- and drug screening approaches to identify critical vulnerable points in CEBPA-mutant AML development and progression.

Anaplastic Large Cell Lymphoma (ALCL)

ALCL is a highly malignant form of Non-Hodgkin’s lymphoma and frequently associated with a chromosomal translocation generating the oncogenic fusion protein NPM-ALK. We take advantage of a NPM-ALK transgenic mouse model for ALCL lymphomagenesis driven by the human CD4 promoter (Chiarle et al. 2003). These mice develop high malignant T-cell lymphomas. Human ALCLs were recently shown to constitutively overexpress the AP-1 proteins c-Jun and JunB. The role of c-Jun and JunB in T-cell lymphomas has not been fully understood.

Prostate Cancer

We established 4 tissue arrays of 8 prostate cancer patients before and 8 patients after androgen ablation therapy, as well as 2 prostate samples from non-tumor affected prostates as controls. To compare the expression levels of candidate oncogenes from patients without prostate cancer (PC), normal prostate tissue was included from prostates of patients that underwent a cystectomy operation. Target gene expression analysis was performed using immunofluorescence microscopy and digital image analysis techniques from our Partner TissueGnostics.

Acute Lymphoblastic Leukemia

In childhood B-ALL the t(12;21)(p13;q22) chromosomal translocation represents the most frequent rearrangement with an incidence of up to 25% in pediatric patients. The chromosomal translocation results in the ETV6/RUNX1 fusion gene, which is assumed as the “first hit” in ETV6/RUNX1 positive B-ALL, but additional genetic alterations are required for the manifestation of the leukemia. Our goal is to identify secondary hits by developing mouse models for this fatal disease.

Hematopoietic Cancer

We are studying normal and abnormal hematopoiesis. We and others have described an essential role for STAT5 activation (for overview see Moriggl & Ferbeyre, BBA, 2011) in the regulation of survival genes in myeloid leukemias with a link to PI3K-AKT-mTOR activation. We were the first to link serine phosphorylation and oligomerization of STAT5 to myeloid transformation. We have related the findings to human MPN and our current work is dissecting how pYSTAT5 synergizes with loss of PTEN. 

Liver Cancer and Metabolism

We have established and molecularly mapped the close interaction of a nuclear hormone receptor, namely the glucocorticoid receptor (GR), with hepatic STAT5 that is largely but not exclusively triggered by hepatic activation of JAK2 kinase. Disruption of the GR-JAK2-STAT5 signaling axis causes metabolic syndrome with aggressive liver cancer development in the case of GR/STAT5 deletion but surprisingly not in the case of JAK2 deletion.

AKT and breast tumors

AKT/PKB is a family of serine-threonine kinases activated in response to growth stimuli downstream of the PI3K /PTEN pathway. The AKT family consists of three members: AKT-1, AKT-2 and AKT-3, and has been implicated in different malignancies, such as glioblastoma, ovarian, gastric, colorectal, prostate and breast tumors. Gene amplification and/or over-activation of the three AKT members have been found in different tumors.