Nuclear Architecture in Leukemia
The main goal of our lab is to understand the molecular mechanisms that induce and control the malignancy of leukemic cells. For that, we combine and integrate state-of-the-art genomics technology, genome-engineering tools, optogenetic and advanced microscopy imaging to study gene regulatory network in human leukemic cells. We focus particularly in the role of the three-dimensional (3D) genome organization in leukemic phenotype and how fusion protein induced by chromosomal translocation can alter the chromatin organization. Beyond our fundamental discoveries, we aim to uncover new targets and biomedical applications for the treatment of lymphoid malignancies.
Understanding the mechanisms that control cell identity and gene regulation and whether they can be used therapeutically are fundamental objectives of current biomedical science. Indeed, the precise regulation of gene expression is crucial to guarantee tissue homeostasis and its alteration drives cell disorders and diseases. In addition to transcription factors and chromatin modifiers, the 3D genome organization has recently emerged as an instrumental player of gene regulation. Indeed, the genome is highly organized into the nucleus into various structures including compartments, domains and loops. These structures are crucial to maintain the physical interactions between regulatory regions and the gene expression. The comprehensive integration of the 3D genome organization with other layers of the gene regulatory network is therefore crucial to uncover the molecular mechanisms beyond the disease and identify new potential therapeutic targets.
Important efforts have been made to define the basis of acute lymphoblastic leukemia (ALL) and identify the genetic lesions contributing to leukemogenesis. The most common mutations affect transcription factors or chromatin modifiers. Particularly, chromosomal translocations that create chimeric transcription factors are often associated to ALL. These mutations alter the protein functions, modify the transcriptional program and initiate the leukemogenesis. In the lab we investigate the multiple layers of the gene regulatory network to understand the dysregulation provoked by mutant proteins and its role in the pathogenesis.
More specifically, the research in our lab is developed around the following axes:
- Uncovering the biophysical properties of the chimeric E2A-PBX1 oncogene and its role on 3D genome alteration and pathogenesis of B cell acute leukemia
We are developing new research lines to explore the molecular mechanisms driving nuclear organization of cancer cells, focusing on chimeric transcription factors generated by chromosomal translocation and its impact on 3D genome organization and pathogenesis. Our recent findings suggest that the chimeric protein E2A-PBX1, associated with one of the most frequent B-acute lymphoid leukaemia (B-ALL) translocations, has liquid-liquid phase separation (LLPS) properties that can drive the alteration of the 3D genome organization and induce leukemogenesis. We combine and integrate multi-omics experimental and computational approaches encompassing state-of-the-art technologies (chromatin conformation capture, NGS, genome editing, degron system, optogenetic, advance microscopy) to elucidate the role of the chimeric protein E2A-PBX1 on 3D chromatin organization and B-ALL malignancy. Understanding how translocation can affect biochemical properties of protein and alter the genome organization and the gene expression will offer potential new biomedical applications for the treatment of haematological malignancies.
- Identification and characterization of genome topology alteration in B cell acute lymphoblastic leukaemia
Recent advances in the molecular approaches to capture the chromosome 3D conformation are improving the current appreciation of how genome architecture affect its function in distinct tissues and diseases. Long-range chromatin interactions are organized in different layers from chromatin compartments to topologically associated domains and chromatin loops at the highest resolution. These 3D features are known to play a role in constraining gene expression patterns. In cancer cells, alteration of the genome topology also impacts gene regulation. Our lab uses a unique model of “cell normalization” of human leukemic cells via transcription factor-mediated transdifferentiation. This process leads to a rewiring of the gene expression pattern, including several oncogenes. We employ genomics technologies on leukemic cells undergoing a conversion to non-tumorigenic macrophages to study the dynamical interplay between oncogenes expression and key epigenetic regulatory mechanisms including genome topology. The impact of proposed 3D genome features on the leukemic phenotype using genome editing techniques followed by in vitro and in vivo assays. Our study aims to generate significant insights about the role of architectural features of the genome during cancer development and to contribute in designing novel therapeutic strategies to treat cancer.
- Characterization of transcription factor mutations and their role in 3D genome organization alteration and leukemogenesis
Somatic alterations of the lymphoid transcription factors (TFs) PAX5 and BCL11b are hallmarks of B and T cell precursor ALL, respectively. While many of these somatic mutations have been classified, their impacts on the molecular mechanisms of the TFs remain elusive. Therefore, we focus on mutation altering domains essential to the biochemical properties of the TFs and evaluate how these mutations affect their properties and the ability of the TFs to shape the genome. We aim to precisely profile the aberrant function of the TFs and to link it to the altered gene regulatory network observed in disease.
2022 Ramón y Cajal Fellowship
2019 “Investigador” Individual Fellowship from the Spanish association against the cancer (AECC).
2017 Marie Skłodowska Curie Individual Fellowship
The trophectoderm acts as a niche for the inner cell mass through C/EBPα-regulated IL-6 signaling.Stem Cell Reports 13 Sep 2022, 17 (9) 1991-2004. Epub 11 Aug 2022
Severe COVID-19-associated variants linked to chemokine receptor gene control in monocytes and macrophages.Genome Biol 14 Apr 2022, 23 (1) 96. Epub 14 Apr 2022
CTCF chromatin residence time controls three-dimensional genome organization, gene expression and DNA methylation in pluripotent cells.Nat Cell Biol Aug 2021, 23 (8) 881-893. Epub 29 Jul 2021
CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.Nat. Genet. 8 Jun 2020, . Epub 8 Jun 2020
Whsc1 links pluripotency exit with mesendoderm specification.Nat Cell Biol Jul 2019, 21 (7) 824-834. Epub 24 Jun 2019
Hoxb5, a Trojan horse to generate T cells.Nat Immunol Mar 2018, 19 (3) 210-212. More information
Genome topology alteration in B cell acute lymphoblastic leukaemia.
|Project leader:||Gregoire Stik|