ABSTRACT
Atherosclerosis is a major risk factor for cardiovascular diseases. Hypercholesterolemia has been both clinically and experimentally linked to cardiovascular disease and is involved in the initiation of atherosclerosis. Heat shock factor 1 (HSF1) is involved in the control of atherosclerosis. HSF1 is a critical transcriptional factor of the proteotoxic stress response that regulates the production of heat shock proteins (HSPs) and other important activities such as lipid metabolism. Recently, HSF1 is reported to directly interact with and inhibit AMP-activated protein kinase (AMPK) to promote lipogenesis and cholesterol synthesis. This review highlights roles of HSF1 and HSPs in critical metabolic pathways of atherosclerosis, including lipogenesis and proteome homeostasis.
ABSTRACT
INTRODUCTION: Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm (<5% cases), which has been categorized under myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the recent classification by the World Health Organization. METHODS: We developed a 51-gene (151.5kB) low-cost targeted myeloid panel based on single-molecule molecular inversion probes to comprehensively evaluate the genomic profile of Juvenile myelomonocytic leukemia (JMML). RESULTS: A total of 50 children with clinical and pathological features of JMML were sequenced at high coverage. Among the 50 patients, 44(88%) harbored mutations in one of the RAS/MAPK-pathway genes, most frequently in NRAS (32%), followed by PTPN11 (28%) and NF1 (22%). One-fifth of children had more than one mutation, with 5 cases harboring two RAS pathway mutations. Monosomy 7 was detected in 32% (16) patients, and five of these did not harbor any RAS pathway mutations. Children with monosomy 7 showed shorter overall survival compared with their wild-type counterparts (P = .02). CONCLUSION: Our study highlights that comprehensive genomic profiling identifies at least one mutation in almost 90% of JMML patients. Performing genomic analysis at baseline might help in triaging children with JMML for allogenic stem cell transplant in resource-constrained settings.
