A cutting-edge approach unravels a novel role for CDK6 in leukemic progenitor cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA646386 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12225127.fastq.gz | Fastqsanger.gz | |||
| SRR12225128.fastq.gz | Fastqsanger.gz | |||
| SRR12225129.fastq.gz | Fastqsanger.gz | |||
| SRR12225130.fastq.gz | Fastqsanger.gz | |||
| SRR12225131.fastq.gz | Fastqsanger.gz |
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Project description:The cyclin-dependent kinases (CDK) CDK6 and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (HSCs and LSCs) that exceeds its function as cell-cycle regulator. Although hematopoiesis appears regular under steady state conditions Cdk6-/- HSCs do not efficiently repopulate upon competitive transplantation and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil (5-FU) treatment. We find that activation of HSCs requires CDK6, which interferes with transcription of key regulators including Egr1. The central role of Egr1 is supported by transcriptional profiling of HSCs. The impaired repopulation capacity extends to BCR-ABLp210+ leukemic stem cells. Transplantation with BCR-ABLp210+-infected bone marrow (BM) from Cdk6-/- mice fails to induce disease although recipient mice do harbor LSCs. Egr1 knock-down in cdk6-/- BCR-ABLp210+ LSKs significantly enhances colony formation underlining the importance of the Cdk6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and as essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
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Project description:The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.
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