A5020269855- Acute Myeloid Leukemia Research
- RNA Research and Splicing
- RNA regulation and disease
- RNA modifications and cancer
- Cancer Genomics and Diagnostics
- Immune cells in cancer
- Immune Cell Function and Interaction
- RNA Interference and Gene Delivery
- MicroRNA in disease regulation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Acute Lymphoblastic Leukemia research
- CAR-T cell therapy research
- Single-cell and spatial transcriptomics
- Immunotherapy and Immune Responses
- Spaceflight effects on biology
- Hematopoietic Stem Cell Transplantation
- Chronic Myeloid Leukemia Treatments
- CRISPR and Genetic Engineering
- Electron Spin Resonance Studies
- Genomics and Phylogenetic Studies
- Hematological disorders and diagnostics
- Cancer-related gene regulation
- Inflammatory Bowel Disease
- Eosinophilic Disorders and Syndromes
- Genomic variations and chromosomal abnormalities
University of California, San Diego
2019-2025
UC San Diego Health System
2025
Oncode Institute
2023-2024
Princess Máxima Center
2021-2024
Sanford Consortium for Regenerative Medicine
2019-2024
Cancer Center Amsterdam
2021-2023
Amsterdam UMC Location Vrije Universiteit Amsterdam
2015-2023
Amsterdam University Medical Centers
2020-2022
University of Antwerp
2020
University of Lausanne
2016
Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation therapeutic resistance in 20 malignancies. Previously, predicting ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 splicing reporters for...
Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements associated with autism spectrum disorders mirror phenotypes obesity/underweight macrocephaly/microcephaly. Such were previously non-overlapping proximal 600 BP4-BP5 interval. These two CNV-prone regions at reciprocally engaged in complex chromatin looping, as...
Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification acute myeloid leukemia (AML) warrants further investigation. To gain more insight into characteristics patients with AML carrying SF mutations, we studied association clinical features, cytogenetic and molecular abnormalities, outcome a large cohort 1447 high-risk myelodysplastic syndrome. were identified 22% associated multiple...
Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations mis-splicing fuel therapy-resistant stem cell (LSC) generation in adults, deregulation has not been extensively studied pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses FACS-purified hematopoietic progenitor cells followed differential dual-fluorescence lentiviral...
Inflammatory cytokine responsive apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC3) cytosine deaminases have been shown to be deregulated during cancer evolution, presenting as gene expression changes and inclusion of distinct C-to-T mutation patterns. However, the exact mechanisms by which APOBEC3 enzymes promote initiation progression remain investigated, especially in hematopoietic malignancies. Building on our advanced sequencing data healthy, pre-leukemic,...
Abstract Background: Essential for preventing autoinflammation, adenosine deaminase acting on double-stranded RNA (ADAR1) is also a recognized driver of epi-transcriptomic remodeling and tumor immune silencing. High levels ADAR1 have been associated with worse prognosis reduced survival in patients high-grade breast cancer (BC), especially the HER2+ triple-negative BC (TNBC) subgroup, which are most likely to develop brain metastasis (BrM), arising up 30% TNBC cases. Nevertheless, role...
Abstract Introduction: B cell acute lymphoblastic leukemia (B ALL) is the most common childhood malignancy with more than ninety percent cure rates and current research efforts are directed towards development of curative therapy in patients who relapse. Leukemia stem (LSC) persistence contributes to Whole genome sequencing RNA (RNA seq) have revealed APOBEC3C ADAR1 base deaminase induced splicing alterations LSCs both adult pediatric myeloid leukemia. Through our study we strive determine...
Abstract Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC)-derived disorders that often arise as a result of JAK2/STAT3 signal activating mutations. In the setting microenvironmental inflammatory cytokines, MPNs also acquire splicing alterations associated with progression to rapidly lethal secondary acute myeloid leukemia (sAML) (reviewed in Jamieson, Weisman. NEJM. 2023). By performing whole genome and RNA sequencing analyses MPN progenitor populations (HSPCs),...
Abstract Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment may likelihood response cell-directed immunotherapies. Understanding composition, phenotype, spatial organization cells other microenvironmental populations in pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion...
Detection of somatic mutations in single cells has been severely hampered by technical limitations whole-genome amplification. Novel technologies including primary template-directed amplification (PTA) significantly improved the accuracy single-cell sequencing (WGS) but still generate hundreds artifacts per reaction. We developed a comprehensive bioinformatic workflow, called PTA Analysis Toolbox (PTATO), to accurately detect base substitutions, insertions-deletions (indels), and structural...
Abstract Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment may likelihood response cell-directed immunotherapies. Understanding composition, phenotype, spatial organization cells other microenvironmental populations in pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion...
Recently, significant advances have been made in the development of splicing modulators for therapeutic purposes.In this respect, several studies demonstrated that acute myeloid leukemia (AML) cells carrying spliceosome mutations are preferentially sensitive to Splicing Factor 3B subunit 1 (SF3B1) modulation [1][2][3].Whereas ~15% AML patients class genes, disruption appears be a global phenomenon hematological malignancies [4].Therefore, we aim identify additional patient subgroups which...
Abstract Detection of somatic mutations in single cells has been severely hampered by technical limitations whole genome amplification. Novel technologies including primary template-directed amplification (PTA) significantly improved the accuracy single-cell sequencing (WGS), but still generate hundreds artefacts per reaction. We developed a comprehensive bioinformatic workflow, called PTA Analysis Toolkit (PTATO), to accurately detect base substitutions, small insertions and deletions...
Despite substantial progress achieved in unraveling the genetics of AML past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate phenotypic features cells further improve response predictions and find innovative therapeutic approaches. In this respect, aberrant splicing a crucial contributor pathogenesis hematological malignancies. Thus far, altered well characterized relation factor AML. However,...
Abstract Introduction Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) derived disorders that can progress to acute myeloid leukemia (AML) at variable rates depending on macroenvironmental stressors and microenvironmental inflammatory cytokines. The total symptom score (TSS) variant allele frequency (VAF) of mutations have proven valuable predictors therapeutic response. Recently, we discovered inflammatory-cytokine-responsive ADAR1 RNA editing enzyme...
Stem cell aging is accelerated by macroenvironmental and microenvironmental stressors, including inflammation. Previously, the NASA Twins study revealed inflammatory cytokine upregulation, chromosomal alterations, telomere changes suggestive of in low-Earth orbit (LEO). To investigate effects spaceflight on human hematopoietic stem progenitor (HSPC) aging, NASA-supported Integrated Space Cell Orbital Research team performed four independent 30- to 45-day missions with matched flight ground...