OUR RESEARCH
p53 PATHOBIOLOGY
Tumor suppressor gene 53 (TP53) is the most frequently altered gene in human cancer with approximately 50% of tumors carrying mutations or deletions in TP53. Unlike other tumor suppressors that typically undergo bi-allelic inactivation through frame-shift mutations or deletions, most mutations in TP53 are missense mutations.
It has recently been demonstrated that not neomorphic gain-of-function (GOF) activities but a dominant-negative effect (DNE) drives the selection of TP53 missense mutations in myeloid malignancies (Boettcher et al., Science 2019).
This finding has important implications: Is the DNE the major driver of TP53 missense mutations in tumors originating in other tissues? How exactly does missense mutant p53 exert a DNE on wild-type p53 in heterozygous cells? Why are the frequencies of TP53 missense mutations so variable in the different tumor types? Can we directly target missense mutant p53 via proximity-induced pharmacological interventions and / or indirectly via synthetic lethality-inducing approaches?
We are addressing these and other questions related to p53 pathobiology using state-of-the-art experimentation involving CRISPR-mediated genome editing, proteomics, and unbiased genetic screening approaches, and in vivo modelling in mice.
CLONAL HEMATOPOIESIS
Tumorigenesis is a stepwise process characterized by the sequential acquisition of oncogenic mutations over years and decades. The existence of a pre-malignant phase – a state where nascent tumors have not yet acquired full oncogenicity – has long been postulated and exemplified by the classic adenoma-carcinoma sequence in colorectal cancer. However, only recently have we begun to gain a better insight into the prevalence and genetic landscape of pre-malignancies in tissues and in the general human population (Jaiswal et al., NEJM 2014; Martincorena et al., Science 2015; Martincorena et al., Science 2018).
Therefore, our principal aims are: (1) To describe the epidemiology pre-malignant lesions in the prototypic somatic stem cell-maintained hematopoietic system (i.e., clonal hematopoiesis of indeterminate potential (CHIP)); (2) To dissect the mechanisms of clonal selection and clonal evolution of pre-malignant blood cells over time; (3) To devise pre-emptive therapeutic strategies in order to prevent malignant transformation in individuals with clonal hematopoiesis.
In order to achieve these goals, we combine epidemiological and genetic studies with hypothesis-driven experimentation as well as discovery-driven high-throughput screening approaches.
LEUKEMOGENESIS
We investigate how acute myeloid leukemia (AML) arises and persists, with a particular focus on the most challenging clinical subtype: TP53-mutant AML. Mutations in TP53 disrupt the fundamental tumor suppressor p53 fostering chromosomal instability, therapy resistance, and dismal clinical outcomes.
Our lab aims to understand how TP53 loss or mutation reshapes hematopoietic stem and progenitor cell fates, remodels the immune microenvironment in the bone marrow, and cooperates with additional mutations to drive leukemic transformation and relapse.
Key open questions include: Which cell populations serve as the cell of origin in TP53-mutant AML? How do TP53-mutant leukemia-initiating cells evade immune surveillance and resist conventional and novel therapies including immunotherapeutic approaches such as CAR T-cells? And which vulnerabilities can be exploited for more efficacious and precise treatments?
To address these questions, we combine classical cell biology, CRISPR-based genome engineering and single-cell technologies with functional assays in human AML cell lines, primary patient samples, and novel in vitro and in vivo mouse models.
By integrating mechanistic studies with clinically annotated cohorts, we aim to translate fundamental insights into therapeutic strategies that improve outcomes for patients with TP53-mutant AML.
