Výzkum

Hematopoietic stem cells, myeloid cells, transcription factors, inflammation, leukemias

In our research group we investigate the regulation of hematopoietic stem cell (HSC) maintenance and fate by transcription factors and their target genes, determine whether these elements are altered in human leukemias (in particular acute myeloid leukemia, AML), and elucidate their contribution to leukemogenesis. Our three main research lines are:

1. Function of C/EBPα target genes in normal and malignant hematopoiesis:
Minute changes in expression of transcription factors deregulate hematopoiesis and aberrations in myeloid transcription factors have been observed in AML patients. One of the key families of myeloid transcription factors is the CCAAT/enhancer-binding proteins (C/EBPs), in which six core members have been identified: C/EBPα, C/EBPβ, C/EBPδ, C/EBPε, C/EBPγ and C/EBPζ. In the hematopoietic system, C/EBPα plays a crucial role in HSC fate and the commitment of multipotent progenitor cells into the myeloid lineage. Defects in CEBPA, such as differentiation-deficient mutations, post-transcriptional modifications, post-translational inhibition and epigenetic regulation, have been shown to inhibit C/EBPα function in AML. Using gene expression profile and chromatin-immunoprecipitation followed by sequencing, we identified novel C/EBPα target genes (Fig.1). Interesting target genes are further analyzed using biochemical and functional assays to determine their role in normal and aberrant hematopoiesis. Currently, our laboratory investigates the function of 2 C/EBPα target genes that so far have not been characterized in HSC maintenance and fate: the transcription factor C/EBPγ (Fig.2) and the transmembrane protein Evi2b (Fig.3).

2. Function of β-catenin/TCF pathway in normal and malignant hematopoiesis:
Hematopoiesis is a continuous and tightly regulated process in which HSCs develop into mature blood cells. The HSC pool is limited and their integrity needs to be preserved throughout life. HSC reside in the bone marrow niche, which provides proper signals for HSC survival, self-renewal, migration and differentiation. Several pathways are involved in these processes, such as the BMP, Notch, TGFβ/SMAD, and JAK/STAT. However, one of the critical yet controversial pathways is the Wnt signaling pathway. A central player in the canonical Wnt signaling cascade is β-catenin, a cytoplasmic protein that in the absence of Wnt signaling is targeted to degradation. Upon Wnt stimulation, Wnt proteins bind to their receptors, subsequently b-catenin gets stabilized, accumulates in the cytoplasm, and translocates to the nucleus where it binds to Tcf/Lef (T cell factor/Lymphoid enhancer factor) transcription factors. Consequently, the Tcf/Lef transcription factors change form a repressive to an active state, inducing transactivation of Wnt target genes. In our laboratory, we are investigating the role of Tcf/lef factors in HSC maintenance and fate, as well as the contribution of these proteins to leukemia development.

3. Effects of chronic inflammation in HSC maintenance and fate:
Traditionally, leukemia has been understood as a two hit model, affecting genes involved in both differentiation and proliferation. Surprisingly, the role of cell extrinsic factors in leukemogenesis has been underestimated. Recent clinical data, though, indicate that patients suffering from chronic inflammation present a significant increase in the risk of leukemia. In our laboratory, we aim to determine how chronic inflammation affects myelopoiesis and determine whether and how it increases the susceptibility to AML.

 

Poslední změna: 3. prosinec 2019