A5063546246- Acute Myeloid Leukemia Research
- Hematopoietic Stem Cell Transplantation
- Immune Response and Inflammation
- Immune cells in cancer
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- CRISPR and Genetic Engineering
- Multiple Myeloma Research and Treatments
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immune Cell Function and Interaction
- Chronic Myeloid Leukemia Treatments
- PARP inhibition in cancer therapy
- T-cell and B-cell Immunology
- DNA Repair Mechanisms
- Hematological disorders and diagnostics
- CAR-T cell therapy research
- Histone Deacetylase Inhibitors Research
- Blood disorders and treatments
- Cancer-related Molecular Pathways
- RNA Interference and Gene Delivery
- Immune responses and vaccinations
- Single-cell and spatial transcriptomics
- Peptidase Inhibition and Analysis
- Evolution and Genetic Dynamics
University Hospital of Zurich
2015-2025
University of Zurich
2019-2025
University Hospital in Halle
2024
Dana-Farber Cancer Institute
2018-2023
Broad Institute
2018-2023
Brigham and Women's Hospital
2013-2023
Harvard University
2013-2023
Dana-Farber Brigham Cancer Center
2023
Massachusetts Institute of Technology
2019
Clinical Research Center Kiel
2013
TP53, which encodes the tumor suppressor p53, is most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic leukemia cell lines of common TP53 mutations. Functional, DNA-binding, transcriptional analyses revealed loss function but no GOF effects. Comprehensive scanning p53 single-amino acid...
Abstract To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. define mechanistic basis clonal hematopoiesis in SDS, investigate somatic mutations acquired by patients SDS followed longitudinally. Here report multiple independent hematopoietic clones arise life, most commonly harboring heterozygous EIF6 or...
Abstract Treatment with Menin inhibitor (MI) disrupts the interaction between and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation loss of survival AML harboring re-arrangement (r) FP, expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, majority patients MLL1-r mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout degradation treatment SNDX-50469 reduces MLL1/MLL1-FP...
Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined an asymptomatic expansion mutant mature hematopoietic cells in ≥4% blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, all-cause mortality. Loss-of-function somatic mutations TET2 are frequent drivers CHIP. However, the contribution aging-associated cooperating cell-extrinsic drivers, like...
Abstract DNA is subject to continual damage, leaving each cell with thousands of individual lesions at any given moment 1–3 . The efficiency repair means that most known classes lesion have a half-life minutes hours 3,4 , but the extent which damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising 818 persisted across multiple cycles in normal human stem cells blood, liver and bronchial epithelium...
Abstract Systemic bacterial infection is rapidly recognized as an emergency state leading to neutrophil release into the circulation and increased myeloid cell production within bone marrow. However, mechanisms of sensing subsequent translation myelopoiesis have not been defined. In this study, we demonstrate in vivo mice that, surprisingly, selective TLR4 expression hematopoietic compartment fails induce LPS-driven myelopoiesis. contrast, TLR4-expressing nonhematopoietic cells are...
Aging is associated with impaired hematopoietic and immune function caused in part by decreased fitness the stem cell (HSC) population an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. Here we demonstrate that older specific pathogen free (SPF) wild-type (WT) mice contrast to young SPF produce more interleukin-1a interleukin-1b (IL-1a/b) steady-state bone marrow (BM), most of IL-1a/b being derived from BM cells....
Abstract Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients relapsed/refractory AML harboring MLL1-r or mtNPM1, but most either fail to respond eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy cells mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations ATAC-Seq RNA-Seq peaks were...
Abstract TP53 -mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for AML/MDS. However, the impact of deficiency in AML cells on efficacy CAR is unknown. We here show that engaging -deficient exhibit prolonged interaction time, upregulate exhaustion markers, inefficient to control cell outgrowth vitro vivo compared...
Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are new class of cancer therapy in active clinical development with evidence activity against acute myeloid leukemia early-phase trials. However, other than activation integrated stress response, downstream effects leading to cell death largely undefined, no murine models available study these agents. We identified domains essential for survival...
Abstract PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover central role for Ppm1d validate potential as therapeutic target. We find regulates competitive fitness self-renewal hematopoietic stem cells (HSCs) with without exogenous genotoxic stresses. also show...
Abstract TP53 -mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing reverse phase protein array datasets revealed significantly lower BAX levels in compared TP53– wild-type (WT) AML, finding confirmed isogenic CRISPR-generated -knockout AML. The response either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent much reduced -WT cells,...
<title>Abstract</title> Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those harvested from a donor, and is received by 40,000 patients worldwide each year. To quantify dynamics of long-term engraftment, we sequenced whole genomes 2,824 single-cell-derived colonies samples 10 donor-recipient pairs taken 9-31 years after HLA-matched sibling HCT. With younger donors, 10,000–50,000 had engrafted were still contributing to...
Abstract Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those from a donor 1,2 . Here, to quantify dynamics of long-term engraftment, we sequenced genomes 2,824 single-cell-derived colonies ten donor–recipient pairs taken 9–31 years after HLA-matched sibling HCT 3 With younger donors (18–47 at transplant), 5,000–30,000 had engrafted and were still contributing haematopoiesis time sampling; estimates tenfold lower older...