Transcriptional dynamics in leukemia
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 approaches, advanced microscopy imaging and single-cell technologies to address questions regarding the integration of hematopoietic differentiation signals with gene regulatory mechanisms. By answering these questions, we aim to uncover vulnerabilities in hematologic malignancies and open new therapeutic opportunities.
Hematopoietic differentiation is a tightly regulated process that maintains blood production throughout life. The transcriptional changes undergone by hematopoietic cells during differentiation are controlled at multiple levels, including transcription factor binding, chromatin modifications or the three-dimensional genome organization. Accurate integration of all these layers is essential to ensure production of sufficient numbers of blood cells at all stages of differentiation. However, a majority of acute myeloid leukemia (AML) cases have mutations in transcriptional regulators and chromatin modifiers. These mutations alter transcriptional dynamics and can impair normal differentiation. To understand how this occurs, we study the mechanisms that regulate transcription during hematopoietic differentiation and investigate the leukemogenic potential of mutations in these proteins.
We have previously studied the role of mutations in the cohesin complex, which are very frequent in AML. We demonstrated that cohesin is required for the transcriptional response to inflammatory signals. Cohesin mutations promote increased resistance to the differentiation-inducing effects of inflammation and alter the normal progress of hematopoietic development. Now we want to expand on these findings and explore how extracellular signalling pathways become uncoupled from transcriptional activity by cohesin mutations and by other frequently mutated transcriptional regulators.
Our main goals are:
- Understand the role of mutations in hematopoietic transcription factors and chromatin regulators in acute myeloid leukemia (AML)
- Characterize the impact of inflammatory signalling on normal hematopoietic differentiation and during leukemic progression
- Single-cell analysis of transcriptional heterogeneity in normal and malignant hematopoietic stem and progenitor cells
We are currently looking for highly motivated Master and PhD students to join our group. Please contact Sergi Cuartero for further information.