Introduction

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.

Our Research

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.

Our Goals

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. Nonetheless, chromosomal translocations that create chimeric transcription factors are often associated also to ALL. These mutations may alter the protein function, modify the transcriptional program and initiate leukemogenesis.

More specifically, the research in our lab develops 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.
• Identification and characterization of genome topology alteration in B cell acute lymphoblastic leukemia. 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.
• Characterization of transcription factor mutations and their role in 3D genome organization alteration and leukemogenesis. We focus on mutation altering domains essential to the biochemical properties of transcription factors (TFs) and evaluate how these mutations affect their properties and the ability to shape the genome. We aim to precisely profile the aberrant function of TFs and link it to the altered gene regulatory network observed in the disease.

Our Challenges

The genome is highly organized in the nucleus into various structures including compartments, domains and loops. These structures are crucial to maintain the physical interactions between regulatory regions and 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.