Molecular Control of Granulocytic Differentiation


We aim to understand the molecular mechanisms of myeloid differentiation

  • to be able to modulate granulopoiesis therapeutically and
  • to better understand crucial aberrations linked to defective differentiation and/or malignant transformation. 

We aim to understand the function of miR-125b during myelopoiesis and in mature granulocytes. 

Research Focus

Steady state granulopoiesis generates large numbers of mature granulocytes in humans. This production can be increased about 20-fold under stress conditions (infection, cytokine stimulation), and emergency granulopoiesis contributes to recovery from bone marrow aplasia. The molecular mechanisms regulating steady-state and emergency granulopoiesis are currently not completely understood but may include different and overlapping signaling cascades (1). Although C/EBPβ is required for steady-state hematopoiesis, cytokine treatment can induce granulopoiesis in the absence of C/EBPβ by induction of C/EBPβ. Furthermore, intracellular NAD+ levels may enhance C/EBPβ and C/EBPβexpression resulting in a positive feed-back loop including G-CSF and G-CSFR (2). 

G-CSFR survival/proliferation signalling can be separated from differentiation signalling. Over-expression of microRNA (miR)-125b e.g. completely blocks G-CSF-induced differentiation of murine 32D myeloid precursor cells but enhances myelopoiesis with generation of mature granulocytes in mouse bone marrow chimeras (3). We identified BAK1, STAT3, c-JUN and JUND as miR-125b regulated target genes which, in combination, contribute to the observed phenotypes. Both 32D/miR-125b and primary miR-125b overexpressing bone marrow cells remain cytokine-dependent demonstrating that miR-125b overexpression does not primarily transform myeloid cells. 

In REBIRTH II, we plan to analyze the effects of miR-125b and the differentiation signals mediated by G-CSFR. We aim to understand the molecular mechanisms of myeloid differentiation to modulate granulopoiesis for transient expansion of myeloid cells. We will study cell proliferation and differentiation of 32D cells with reduced C/EBPβ expression in the presence of miR-125b overexpression. We will compare G-CSF-, GM-CSF/IL-3- and vitamin B3-induced granulopoiesis in primary cells upon overexpression of miR-125b and the function of miR-125b overexpressing granulocytes. These studies will provide information on potential therapeutic targets to regulate emergency granulopoiesis. This knowledge may allow to modulate emergency granulopoiesis by small molecules (such as Vitamin B3 (2)) in the future ex vivo or in vivo

(1) Hirai H, Zhang P, Dayaram T, Hetherington CJ, Mizuno S, Imanishi J, Akashi K, Tenen DG. C/EBPβ is required for 'emergency' granulopoiesis. Nat Immunol. 2006;7(7):732-9. 

(2) Skokowa J, Lan D, Thakur BK, Wang F, Gupta K, Cario G, Brechlin AM, Schambach A, Hinrichsen L, Meyer G, Gaestel M, Stanulla M, Tong Q, Welte K. NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway. Nature Medicine. 2009;15(2):151-8.

(3) Surdziel E, Cabanski M, Dallmann I, Lyszkiewicz M, Krueger A, Ganser A, Scherr M, Eder M. Enforced expression of miR-125b affects myelopoiesis by targeting multiple signaling pathways. BLOOD. 2011;117(16):4338-48. 


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