A5009212994- Acute Myeloid Leukemia Research
- Acute Lymphoblastic Leukemia research
- Protein Kinase Regulation and GTPase Signaling
- Chronic Myeloid Leukemia Treatments
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- Inflammasome and immune disorders
- Retinoids in leukemia and cellular processes
- Cytokine Signaling Pathways and Interactions
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Peptidase Inhibition and Analysis
- Cancer therapeutics and mechanisms
- Immune Cell Function and Interaction
- Immunodeficiency and Autoimmune Disorders
- Microtubule and mitosis dynamics
- Genetics and Neurodevelopmental Disorders
- Protein Degradation and Inhibitors
- Bioactive Compounds and Antitumor Agents
- Signaling Pathways in Disease
- Neuroendocrine regulation and behavior
- Synthesis of Indole Derivatives
- Circadian rhythm and melatonin
- Adenosine and Purinergic Signaling
University of California, San Francisco
2011-2024
Genome Institute of Singapore
2021-2022
Agency for Science, Technology and Research
2021-2022
Pediatrics and Genetics
2020
UCSF Helen Diller Family Comprehensive Cancer Center
2010-2020
Duke-NUS Medical School
2015-2018
UCSF Benioff Children's Hospital
2018
Institute of Biomedical Science
2010
Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry markedly increased risk developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority which were phenotypically normal, from 5 families diagnosed myelodysplasia leukemia syndrome 7 (MLSM7; OMIM 252270) who primarily had onset hematologic abnormalities during first decade life. Molecular analyses uncovered germline (n = 4) or 1) in these families. Affected...
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, PIP4K lipid kinases as target of a131. Ablation PIP4Ks generates phenocopy pharmacological effects inhibition by Notably, a131 causes reversible growth arrest in cells transcriptionally upregulating PIK3IP1, suppressor PI3K/Akt/mTOR pathway....
Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia (AML). It has been hypothesized that MYC protooncogene central importance trisomy 8, but experimental data to support this are limited and controversial. In a mouse model promyelocytic which MRP8 promoter drives expression PML-RARA fusion gene cells, Myc allele gained approximately two-thirds cases as result for 15. We used test idea underlies acquisition AML. retroviral vector drive wild-type,...
Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate biallelic
Arginine vasopressin (AVP) elicits a larger decrease in heart rate for given increase arterial pressure than do other vasoconstrictors, but there is disagreement as to whether this results from an baroreflex gain or resetting of the lower blood pressure. It also unclear which type receptor mediates action on baroreflex. In present study, effects vasopressin, selective V1 and V2 agonists, oxytocin, antagonist control were investigated conscious, chronically prepared rabbits. Baroreflex curves...
Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS) and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germ line deletion of 2-Mb interval chromosome band 5A3 syntenic commonly deleted segment human 7q22 show that mutant hematopoietic cells exhibit cardinal features MDS. Specifically, the long-term stem cell (HSC) compartment is expanded 5A3(+/del) mice, distribution myeloid progenitors altered. HSCs defective...
Supernumerary centrosomes promote the assembly of abnormal spindles in many human cancers. The observation that modest changes centrosomal levels Mps1 kinase can cause centrosome overduplication cells suggests existence a regulatory system may tightly control its stability. Here, we show Cdkn3, Cdk-associated phosphatase, prevents Mps1-mediated overduplication. We identify Cdkn3 as direct binding partner Mps1. interaction between and is required for to recruit centrosomes. Subsequently,...
Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline causes developmental disorders called RASopathies. The mutant proteins encoded by these less biochemically and functionally activated than those cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles characterized the consequences each mutation vivo. Embryonic expression KrasT58I resulted craniofacial abnormalities reminiscent seen RASopathy...
The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to inner membrane, and second endoplasmic reticulum (ER), facilitates translation of nascent polypeptides within ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic loss-of-function variants, including splice-site, nonsense, frameshift, missense variants. These affected...
Abstract Background A trio exome sequencing study identified a previously unreported NLRP1 gene variant resulting in p.Leu813Pro substitution of the LRR (leucine-rich repeats) domain protein (NACHT, and PYD domains-containing 1). This homozygous mutation was shared by two sisters with different clinical presentation: younger sister had generalized inflammatory nodules keratotic plugs, clinically resembling multiple keratoacanthomas, while older manifestations familial keratosis lichenoides...
Abstract Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate biallelic DPP9 rare variants. Using patient-derived primary cells biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles fail repress NLRP1. Remarkably, the removal mice,...
The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis cancer into improved therapies. Insertional mutagenesis (IM) in mice robust strategy for generating malignancies that recapitulate extensive inter- and intra-tumoral genetic heterogeneity found advanced human cancers. While central role "driver" viral insertions IM aberrantly increase expression proto-oncogenes or disrupt tumor suppressors has been appreciated many...
Abstract Monosomy 7 and del(7q) are among the most common poorly understood genetic alterations in myelodysplastic neoplasms acute myeloid leukemia. Chromosome band 7q22 is a minimally deleted segment malignancies with del(7q). However, rarity of “second hit” mutations supports idea that del(7q22) represents contiguous gene syndrome. We generated mice harboring 1.5 Mb germline deletion chromosome 5G2 syntenic to human removes Cux1 27 additional genes. Hematopoiesis perturbed +/del but they...