AG Feuring - Buske

Working Program

Ongoing Projects:

  1. VENTX: a novel regulator in human leukemias
    Previously, we have shown that human Vent-like homeobox gene VENTX, a putative homologue of the early developmental Xenopus xvent2 gene, is a novel regulatory hematopoietic gene. We could document that enforced VENTX expression promotes myeloid development while paralleled by downregulation of lymphoid development genes. VENTX is aberrantly expressed in CD34+ leukemic stem cell (LSC) candidates in human AML, predominantly in t(8;21) positive and normal karyotype (NK) AML.  Lentiviral mediated knock-down of VENTX in human AML cell lines significantly impaired leukemic cell growth, indicating that VENTX is a key protein for human leukemic growth. Based on these findings we want to evaluate the regulatory function of VENTX by analyzing upstream regulators and downstream targets of VENTX in leukemic hematopoiesis. We want to identify factors which contribute to the aberrant expression of VENTX in LSC and evaluate the functional relevance. Furthermore, we want to analyze a potential collaboration of VENTX with AML1-ETO in perturbing hematopoiesis and evaluate the role of the known VENTX pseudogenes in leukemic transformation.  Finally, we want to search for potential therapeutic strategies to inhibit aberrant VENTX expression in CD34+ LSC´s.
    Co-investigator: V. Rawat
    Collaborator:  C. Buske, H. Döhner, K. Döhner, F.  Kuchenbauer all from Germany
  2. Proteins involved in the organization of microtubular signalling complexes such as PBXIP1/HPIP can act as regulators of early human hematopoiesis.
    The hematopoietic PBX-interacting protein (HPIP) was identified by a yeast two-hybrid screen of a fetal-liver hematopoietic cDNA library using PBX1 as a bait. The amino acid sequence of HPIP-wt harbours the LxxLL domain, that has been identified previously in protein-protein interactions associated with the transcriptional regulation and also in hormone signaling. HPIP shows many characteristics which point to a potential role of the protein in hematopoietic development, as e.g. its high expression levels in human hematopoietic progenitors, its ability to interact and transcriptionally repress the PBX1 homeobox gene, which itself is an important partner of hematopoietic active HOX genes, and finally its function as an organizer of the microtubule signalling complex. Thus, we ask whether HPIP might be a yet unidentified regulatory protein in early human hematopoiesis as well as leukemogenesis.
    Collaborator: C. Buske, H. Döhner, K. Döhner, Rawat, R.K.Humphries
  3. Micro RNA profiling of leukemic stem cell candidates
    To further evaluate potential differences between normal and leukemic stem cell candidates we analyze non-coding RNAs in sorted subfractions of patients with acute myeloid leukemia. The functional role of differentially expressed micro RNAs in hematopoietic stem and progenitor cells will be analyzed using in vivo and in vitro model systems.
    Collaborator: C. Buske, H. Döhner, K. Döhner

  4. Role of aberrantly expressed lymphoid antigens in patients with acute myeloid leukemia
    Multi-parameter flow cytometry together with molecular genetics and cytogenetic studies have all contributed to a new classification of leukemia. Aberrant antigen expression in acute myeloid leukemia (AML) has been extensively studied over the past years. However, limited knowledge has been obtained regarding the functional significance of these expression patterns for the pathobiology of the disease. Using our functional in vitro and in vivo models we analyze the pathobiological significance of aberrantly expressed lymphoid antigens.
    Collaborator: C. Buske, H. Döhner, K. Döhner