New regulatory mechanism of myelopoiesis

Objectives

Our main aims are: 

  • to study the regeneration of hematopoiesis using nicotinamide (vitamin B3), NAMPT and sirtuins; 
  • to identify substances capable to activate hematopoietic-specific Lyn substrate-1 protein (HCLS1) for the regeneration of myelopoiesis; 
  • to identify the tools for the correction of myeloid differentiation in patients with severe congenital neutropenia using patients-specific iPS cells. 

Research Focus

Since the last 10 years our research group focuses on the identification of the new cytokine receptors signaling systems and on better characterization of known signaling pathways operating during differentiation of hematopoietic stem cells. We are trying to better understand the mechanisms of myeloid differentiation and leukemogenic transformation. We possess a unique collection of clinical data and biological samples of patients with a rare inherited disorder of hematopoiesis, the severe congenital neutropenia (SCN) syndrome. Patients with SCN represent a very well defined group of immune deficiency syndromes with a characteristic hematological phenotype: their bone marrow hematopoietic myeloid progenitor cells, promyelocytes, could not differentiate into mature granulocytes with an accumulation of promyelocytic cells in the bone marrow and the absence of mature granulocytes in the peripheral blood. Therefore, these patients develop severe bacterial infections early after birth and have to be treated with daily subcutaneous injections of the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF). Unfortunately, ca. 20 % of patients with severe congenital neutropenia develop acute myeloid leukemia (AML). We believe, that understanding the processes leading to a „maturation arrest“ of granulocytic progenitor cells in SCN patients may lead to identification of new signaling systems essential for myeloid differentiation of stem cells and to evaluation of new therapeutic tools dealing with better regeneration of the immune system in one inherited disorder of hematopoiesis. Moreover, understanding of the mechanisms of leukemogenic transformation in SCN patients may lead to identification new therapeutic tools for treatment of leukemia. 

Collaborations

  • A. Schambach, REBIRTH Unit Regenerative Gene Therapy: Generation of SCN patients specific iPS cells; generation of LEF-1-/- mouse iPS cells 
  • D. Steinemann REBIRTH Unit Genomic Profiling: Evaluation of leukemogenic gene mutations in CN patients who developed AML
  • T. Moritz REBIRTH Unit iPSC based haematopoietic regeneration: Characterisation of restored granulopoiesis in NSG mice transplanted with gene modified CD34+ hematopoietic cells from patient with alveolar proteinosis
  • R. Grosschedl, Max Planck Institute of Immunobiology and Epigenetics, Freiburg: LEF-1-/- MEFs for the generation of mouse LEF-1-/- iPS cells, postrtranslational modifications of LEF-1 protein 
  • D.C. Dale, University of Washington, Seattle, WA, USA, Co-Director of the Severe Chronic Neutropenia International Registry: Clinical data and material of SCN patients, PPG aplication at NIH 
  • J. Burkhardt, University of Pennsylvania School of Medicine, Philadelphia, USA: Experiments with HCLS1-/- mice
  • Q. Tong, Dept of Medicine, Baylor College of Medicine, Houston, Texas, USA: SIRT-dependent protein deacetylation

Equipment and Service Facilities

[Please find a list of all available equipment here]

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