ORCID Profile
0000-0002-9859-1261
Current Organisations
University of Helsinki
,
Institute for Molecular Medicine Finland
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Publisher: American Society of Hematology
Date: 08-03-2021
DOI: 10.1182/BLOODADVANCES.2020003230
Abstract: Circular RNAs (circRNAs) are dynamically regulated during differentiation and show cell type–specific expression, which is altered in cancer and can have a direct impact on its various hallmarks. We hypothesized that circRNA expression is deregulated in acute myeloid leukemia (AML) and that circRNA candidates might contribute to the pathogenesis of the disease. To identify leukemia-associated and differentiation-independent changes in circRNA expression, we determined the circular RNAome of 61 AML patients and 16 healthy hematopoietic stem and progenitor cell (HSPC) s les using ribosomal RNA–depleted RNA sequencing. We found hundreds of circRNAs that were differentially expressed between AML and healthy HSPCs. Gene set analysis found that many of these circRNAs were transcribed from genes implicated in leukemia biology. We discovered a circRNA derived from the T-cell transcription factor gene B cell CLL/lymphoma 11B, circBCL11B, which was exclusively expressed in AML patients, but not detected in healthy HSPCs, and associated with a T-cell–like gene expression signature. We were able to validate this finding in an independent cohort of 332 AML patients. Knockdown of circBCL11B had a negative effect on leukemic cell proliferation and resulted in increased cell death of leukemic cells, thereby suggesting circBCL11B as a novel functionally relevant candidate in AML pathogenesis. In summary, our study enables comprehensive insights into circRNA expression changes upon leukemic transformation and provides valuable information on the biology of leukemic cells and potential novel pathway dependencies that are relevant for AML therapy.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
Publisher: The Endocrine Society
Date: 25-02-2019
Abstract: The risk for dementia among subjects who are obese with normal metabolic profiles, or called metabolically healthy obese (MHO), remains uninvestigated. To determine the association between late-life metabolic health and obesity status and risk of incident dementia. Retrospective cohort study. The National Health Insurance System, Republic of Korea. A total of 12,296,863 adults >50 years old who underwent health examinations from 2009 to 2012 without baseline history of dementia. Incident overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Among subjects ≥60 years old, 363,932 (6.4%) developed dementia during a median follow-up of 65 months (interquartile range 51 to 74 months). The MHO group showed the lowest incidence of overall dementia [hazard ratio (HR) 0.85 95% CI, 0.84 to 0.86] and AD (HR 0.87 95% CI, 0.86 to 0.88), but not VaD, compared with the metabolically healthy nonobese group. All components of metabolic syndrome except obesity significantly elevated the risk of dementia, and these associations were more pronounced in VaD. In particular, being underweight dramatically increased the risk of dementia. The MHO phenotype in late life demonstrated lower risk of overall dementia and AD but not VaD. Additional studies in other populations are warranted to elucidate current results and may predict in iduals most at risk for developing dementia.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 29-09-2017
Publisher: Springer Science and Business Media LLC
Date: 02-05-2019
DOI: 10.1038/S41467-019-09745-2
Abstract: Mutations in the nucleophosmin 1 ( NPM1 ) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated ( NPM1 mut ) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1 mut s les obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1 mut loss ( n = 11). To better understand these NPM1 mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1 mut loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis s le and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1 mut are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1 mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of relapse.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Tamara Jacqueline Luck.