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CDK6 as key regulator of hematopoietic and leukemic stem cell activation.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE62012 | GEO | 2015/02/20

SECONDARY ACCESSION(S): PRJNA262936

REPOSITORIES: GEO

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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.

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CDK6 as key regulator of hematopoietic and leukemic stem cell activation.

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