Contributions
Abstract: PB1383
Type: Publication Only
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
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 two-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs, and the significant toxicity towards healthy hematopoietic cells. Whilst much work has been done to identify genetic and epigenetic vulnerabilities in AML LSCs, little is known about protein dynamics and the role of protein degradation in drug resistance and relapse.
Aims
- Delineate the roles of CKS1 in normal and malignant hematopoietic stem cells.
- Develop new strategies to specifcally target AML LSCs.
- Investigate critical roles for CKS1 in LSC intracellular signalling pathways.
Methods
.
Results
Using a highly specific inhibitor of the SCFSKP2-CKS1complex, we present a dual role for CKS1-dependent protein degradation in reducing AML blasts in vivo, and importantly depleting LSCs. Whilst many AML LSC targeted therapies show significant toxicity to healthy hematopoiesis, inhibition of CKS1-dependent protein degradation has the opposite effect, protecting normal hematopoietic cells from chemotherapeutic toxicity. Together these findings demonstrate CKS1-dependent proteostasis is key for normal and malignant stem cell biology.
Conclusion
The inhibition of CKS1-dependent protein degradation holds excellent promise for AML therapy, both as a single agent towards CKS1BhighAML, and in combination with induction chemotherapy in other AML cases. Reports of CKS1B overexpression correlating with outcome in other solid cancer types, novel ways to modulate CKS1, and the development of more clinically ready molecules to target CKS1, indicate that proteostatic targeting, through the CKS1/CKS2 axis, holds much hope for future cancer therapy.
Keyword(s): AML, Hematopoietic stem cell, Leukemic stem cell, Proteomics
Abstract: PB1383
Type: Publication Only
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
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 two-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs, and the significant toxicity towards healthy hematopoietic cells. Whilst much work has been done to identify genetic and epigenetic vulnerabilities in AML LSCs, little is known about protein dynamics and the role of protein degradation in drug resistance and relapse.
Aims
- Delineate the roles of CKS1 in normal and malignant hematopoietic stem cells.
- Develop new strategies to specifcally target AML LSCs.
- Investigate critical roles for CKS1 in LSC intracellular signalling pathways.
Methods
.
Results
Using a highly specific inhibitor of the SCFSKP2-CKS1complex, we present a dual role for CKS1-dependent protein degradation in reducing AML blasts in vivo, and importantly depleting LSCs. Whilst many AML LSC targeted therapies show significant toxicity to healthy hematopoiesis, inhibition of CKS1-dependent protein degradation has the opposite effect, protecting normal hematopoietic cells from chemotherapeutic toxicity. Together these findings demonstrate CKS1-dependent proteostasis is key for normal and malignant stem cell biology.
Conclusion
The inhibition of CKS1-dependent protein degradation holds excellent promise for AML therapy, both as a single agent towards CKS1BhighAML, and in combination with induction chemotherapy in other AML cases. Reports of CKS1B overexpression correlating with outcome in other solid cancer types, novel ways to modulate CKS1, and the development of more clinically ready molecules to target CKS1, indicate that proteostatic targeting, through the CKS1/CKS2 axis, holds much hope for future cancer therapy.
Keyword(s): AML, Hematopoietic stem cell, Leukemic stem cell, Proteomics