30 research outputs found
Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia
The Brazilian National Council for Scientific and
Technological Development), Bloodwise, Children with Cancer and MRC (Medical
Research Council, UK)
Proteomic and genomic integration identifies kinase and differentiation determinants of kinase inhibitor sensitivity in leukemia cells
CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia
Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low 2-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs and toxicity of therapy toward healthy hematopoietic cells. We studied the role of cyclin-dependent kinase regulatory subunit 1 (CKS1)-dependent protein degradation in primary human AML and healthy hematopoiesis xenograft models in vivo. Using a small-molecule inhibitor (CKS1i), we demonstrate a dual role for CKS1-dependent protein degradation in reducing patient-derived AML blasts in vivo and, importantly, depleting LSCs, whereas inhibition of CKS1 has the opposite effect on normal hematopoiesis, protecting normal hematopoietic stem cells from chemotherapeutic toxicity. Proteomic analysis of responses to CKS1i in our patient-derived xenograft mouse model demonstrate that inhibition of CKS1 in AML leads to hyper-activation of RAC1 and accumulation of lethal reactive oxygen species, whereas healthy hematopoietic cells enter quiescence in response to CKS1i, protecting hematopoietic stem cells. Together, these findings demonstrate that CKS1-dependent proteostasis is a key vulnerability in malignant stem cell biology.Peer reviewe
Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma
We are indebted to the patients for donating
tumor specimens as part of this study. The authors thank the Centre de
Ressources Biologiques (CRB)-Santé of Rennes (BB-0033-00056) for
patient samples, Queen Mary University of London Genome Centre
for Illumina Miseq sequencing, and the support by the National
Institute for Health Research (NIHR) Biomedical Research Centre at
Guy’s and St Thomas’ NHS Foundation Trust and King’s College
London for Illumina Hiseq sequencing. The views expressed are
those of the authors and not necessarily those of the NHS, the NIHR,
or the Department of Health. This work was supported by grants
from the Kay Kendall Leukaemia Fund (KKL 757 awarded to J.O.),
Cancer Research UK (22742 awarded to J.O., 15968 awarded to J.F.,
Clinical Research Fellowship awarded to S.A.), Bloodwise through
funding of the Precision Medicine for Aggressive Lymphoma (PMAL)
consortium, Centre for Genomic Health, Queen Mary University
of London, Carte d’Identité des Tumeurs (CIT), Ligue National
contre le Cancer, Pôle de biologie hospital universitaire de
Rennes, CRB-Santé of Rennes (BB-0033-00056), and CeVi/Carnot
program
Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants
Bloodwise Program Grant (14032) and the
Medical Research Council Research Grant (MR/P018440)
GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML.
Saudi Arabian Ministry of Higher Education through a doctoral scholarship awarded to A.F.A.S. and a Bloodwise Programme grant (14032) awarded to J.F., T.V., and I.D