Transcriptional dynamics in leukemia
Josep Carreras Leukaemia Research Institute
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona
The main interest of our lab is to understand the mechanisms that regulate transcription during normal and malignant haematopoiesis. We employ a combination of genome-wide techniques, genetic engineering tools and advanced microscopy imaging to reveal the genomic regulatory mechanisms that allow blood cells to integrate extracellular signalling information and implement new transcriptional programs. Our ultimate goal is to find molecular vulnerabilities that uncover new therapeutic strategies to treat myeloid malignancies.
Hematopoietic differentiation is a tightly regulated process that ensures a constant flow of blood cell production throughout our lifetime. The transcriptional changes undergone by hematopoietic cells during differentiation are controlled at multiple levels, including transcription factor binding, chromatin modifications and the three-dimensional (3D) genome organization. Accurate integration of all these layers is essential to ensure production of sufficient numbers of blood cells at all stages of differentiation.
Mutations in genes encoding transcriptional regulators and chromatin modifiers are a major driver of acute myeloid leukemia (AML). The defective function of these mutant proteins alters the normal transcriptional dynamics and impairs normal differentiation, giving rise to the outgrowth of malignant clones. To understand how this occurs, we study the mechanisms that regulate transcription during hematopoietic differentiation and investigate the full spectrum of gene deregulation associated to recurrent AML mutations. More specifically, our main goals are:
- To characterize and understand the main transcriptional and epigenetic events in Down syndrome leukemia. Acute megakaryoblastic leukemia is a pediatric leukemia with a strong incidence in children with trisomy 21. The most frequent genomic alterations include mutations in the transcription factor GATA1 and in three-dimensional genome organizer proteins such as cohesin or CTCF. We are investigating the precise role of these proteins in promoting this disease.
- To investigate the three-dimensional genomic landscape regulating Hox gene expression in normal and malignant haematopoiesis. Hox genes encode a large family of homeodomain-containing transcription factors that are essential for normal hematopoietic development. These genes are located in genomic clusters tightly regulated by specific enhancer elements. This accurate control is lost in many cases of AML and is thought to drive malignant clone expansion. We are characterizing the 3D conformation and enhancer landscape of Hox gene clusters in AML.
- To understand the interplay between myeloid-specific mutations and alterations in signalling pathways commonly observed in myeloid malignancies. Inflammatory signals have a strong influence on blood development, and chronic inflammation has been associated to myeloid diseases such as Myelodysplastic Syndromes (MDS). We are investigating the impact of inflammation on the progression of myeloid malignancies and how they are linked to some of the most common epigenetic mutations.
La Caixa Junior Leader (2020)