tp53 R217H and R242H mutant zebrafish exhibit dysfunctional p53 hallmarks and recapitulate Li-Fraumeni syndrome phenotypes.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germline TP53 mutations. We characterized the first LFS zebrafish hotspot mutants, tp53 R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have defective cell-cycle checkpoints, and display partial-to-full resistance to apoptosis, although the R217H mutation has hypomorphic characteristics. Spontaneous tumor development histologically resembling human sarcomas was observed as early as 6 months.

Arkadia: a new player in hematopoietic stem and progenitor cell development.

Not available.

A dataset of transcriptomic effects of camptothecin treatment on early zebrafish embryos.

Zebrafish () are a good model for cancer research including studies on chemotherapy treatments. We treated wild-type and deletion mutant zebrafish embryos at 24 h post-fertilization with 1 µM of the topoisomerase I inhibitor, camptothecin (CPT), for 4 h to catalogue gene expression changes induced by this DNA damage treatment and to understand if these changes are influenced by loss of miR-34a. The 4 sample groups of 3 independent biological samples consisting of 30 embryos each were analyzed by RNA-sequencing using the recently updated zebrafish transcriptome annotation based on GRCz11, which enabled a more complete and sensitive read mapping and gene assignment than standard annotations.

Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish.

Mutations in the DNAJC21 gene were recently described in Shwachman-Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using the zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth, and defective protein synthesis.

miR-34a is a tumor suppressor in zebrafish and its expression levels impact metabolism, hematopoiesis and DNA damage.

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds.

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.

Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome.

Mutation Knock-in Methods Using Single-Stranded DNA and Gene Editing Tools in Zebrafish.

Introduction or knock-in of precise genomic modifications remains one of the most important applications of CRISPR/Cas9 in all model systems including zebrafish. The most widely used type of donor template containing the desired modification is single-stranded DNA (ssDNA), either in the form of single-stranded oligodeoxynucleotides (ssODN) (<150 nucleotides (nt)) or as long ssDNA (lssDNA) molecules (up to about 2000 nt). Despite the challenges posed by DNA repair after DNA double-strand breaks, knock-in of precise mutations is relatively straightforward in zebrafish.

Tissue-Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition.

Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates.

The Potential Genetic Link behind the Overlap in the Symptomatology between CHARGE and Central Congenital Hypoventilation Syndromes.

CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE syndrome are frequently born with anomalies requiring multiple surgeries and often experience adverse events post-anesthesia, including oxygen desaturations, decreased respiratory rates, and heart rate abnormalities.

Back to the future: evolutionary biology reveals a key regulatory switch in neuroblastoma pathogenesis.

While MYCN expression is an important contributing factor to heterogeneity in the natural history of neuroblastoma (NBL), a mechanistic understanding of this often mutationally quiet tumor has remained elusive. In this issue of the JCI, Weichert-Leahey and authors focused on the adrenergic and mesenchymal core regulatory circuitries (CRC) as NBL transcriptional programs. The authors previously showed that overexpression of LIM-domain-only 1 (LMO1), a transcriptional coregulator, synergizes with MYCN to accelerate tumor formation and metastasis in an NBL-zebrafish model.

S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720.

Hyperactive sphingosine 1-phosphate (S1P) signaling is associated with a poor prognosis of triple-negative breast cancer (TNBC). Despite recent evidence that links the S1P receptor 1 (S1P1) to TNBC cell survival, its role in TNBC invasion and the underlying mechanisms remain elusive. Combining analyses of human TNBC cells with zebrafish xenografts, we found that phosphorylation of S1P receptor 1 (S1P1) at threonine 236 (T236) is critical for TNBC dissemination.

The impact of Down syndrome-specific non-malignant hematopoietic regeneration in the bone marrow on the detection of leukemic measurable residual disease.

Background: Detection of measurable residual disease detection (MRD) by flow cytometry after the first course of chemotherapy is a standard measure of early response in patients with acute myeloid leukemia (AML). Myeloid leukemia associated with Down Syndrome (ML-DS) is a distinct form of AML. Differences in steady-state and regenerating hematopoiesis between patients with or without DS are not well understood.

Loss of in Zebrafish, a Model of Limb-Girdle Muscular Dystrophy, Increases Susceptibility to Muscle Defects Due to Elevated Muscle Activity.

Limb-Girdle Muscular Dystrophy Type R1 (LGMDR1; formerly LGMD2A), characterized by progressive hip and shoulder muscle weakness, is caused by mutations in . In zebrafish, mediates Def-dependent degradation of p53 in the liver and intestines. We show that is expressed in the muscle.

Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models.

Despite numerous therapeutic options, multidrug resistance (MDR) remains an obstacle to successful breast cancer therapy. Jadomycin B, a natural product derived from ISP5230, maintains cytotoxicity in MDR human breast cancer cells. Our objectives were to evaluate the pharmacokinetics, toxicity, anti-tumoral, and anti-metastatic effects of jadomycin B in zebrafish larvae and mice.

Zebrafish models of inflammation in hematopoietic development and disease.

Zebrafish offer an excellent tool for studying the vertebrate hematopoietic system thanks to a highly conserved and rapidly developing hematopoietic program, genetic amenability, optical transparency, and experimental accessibility. Zebrafish studies have contributed to our understanding of hematopoiesis, a complex process regulated by signaling cues, inflammation being crucial among them. Hematopoietic stem cells (HSCs) are multipotent cells producing all the functional blood cells, including immune cells.

Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial.

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.

KIT D816V is dimerization-independent and activates downstream pathways frequently perturbed in mastocytosis.

KIT, a type III tyrosine kinase receptor, plays a crucial role in haematopoietic development. The KIT receptor forms a dimer after ligand binding; this activates tyrosine kinase activity leading to downstream signal transduction. The D816V KIT mutation is extensively implicated in haematological malignancies, including mastocytosis and leukaemia.

Radiation dose enhancement using gold nanoparticles with a diamond linear accelerator target: a multiple cell type analysis.

Radiotherapy (RT) is an effective cancer treatment modality, but standard RT often causes collateral damage to nearby healthy tissues. To increase therapeutic ratio, radiosensitization via gold nanoparticles (GNPs) has been shown to be effective. One challenge is that megavoltage beams generated by clinical linear accelerators are poor initiators of the photoelectric effect.

Stress hematopoiesis induces a proliferative advantage in TET2 deficiency.

TET2 loss-of-function mutations are recurrent events in a wide range of hematological malignancies and a physiologic occurrence in blood cells of healthy older adults. It is currently unknown what determines if a person harboring a somatic TET2 mutation will progress to myelodysplastic syndrome or acute myeloid leukemia. Here we develop a zebrafish tet2 mutant through which we show that tet2 loss leads to restricted hematopoietic differentiation combined with a modest upregulation of p53, which is also characteristic of many inherited bone marrow failure syndromes.

High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare.

STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.

The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions.

Zebrafish Cancer Predisposition Models.

Cancer predisposition syndromes are rare, typically monogenic disorders that result from germline mutations that increase the likelihood of developing cancer. Although these disorders are individually rare, resulting cancers collectively represent 5-10% of all malignancies. In addition to a greater incidence of cancer, affected individuals have an earlier tumor onset and are frequently subjected to long-term multi-modal cancer screening protocols for earlier detection and initiation of treatment.

Humanized zebrafish enhance human hematopoietic stem cell survival and promote acute myeloid leukemia clonal diversity.

Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α).