Proteomics

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CKS1-dependent proteostatic regulation has dual roles in combating acute myeloid leukemia whilst protecting normal hematopoiesis


ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological disorder comprised of a hierarchy of quiescent leukemic stem cells and fast proliferating blasts with limited self-renewal ability. Significant plasticity in the AML epigenome and metabolome results in a high rate of drug resistance and relapse, with extremely low 2-year survival rates in the poorest cytogenetic risk patients. The current backbone of clinical induction chemotherapy reduces total disease burden, but does not deplete leukemic stem cells which reconstitute the disease in vivo, and also suffers from severe toxicity of healthy hematopoietic cells. Whilst much work has been done to identify epigenetic vulnerabilities in AML, little is known about protein dynamics, and here we explored the therapeutic inhibition of highly specific CKS1-dependent protein degradation. We report a dual role for CKS1-depdent protein degradation in specifically targeting AML, whilst protecting normal hematopoietic cells from chemotherapeutic toxicity.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Pedro Casado-Izquierdo  

LAB HEAD: Pedro R. Cutillas

PROVIDER: PXD022754 | Pride | 2022-07-20

REPOSITORIES: pride

Dataset's files

Source:
Action DRS
F004002.mzid.gz Mzid
F004003.mzid.gz Mzid
F004004.mzid.gz Mzid
F004005.mzid.gz Mzid
F004006.mzid.gz Mzid
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Publications

CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia.

Grey William W   Rio-Machin Ana A   Casado Pedro P   Grönroos Eva E   Ali Sara S   Miettinen Juho J JJ   Bewicke-Copley Findlay F   Parsons Alun A   Heckman Caroline A CA   Swanton Charles C   Cutillas Pedro R PR   Gribben John J   Fitzgibbon Jude J   Bonnet Dominique D  

Science translational medicine 20220622 650


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 regulator  ...[more]

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