Credit: Robert Paulson
Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.
Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.
When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.
However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.
“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.
“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”
Specifically, Scheicher and her colleagues found that Cdk6−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.
Mice that received BCR-ABLp210+–infected bone marrow harvested from Cdk6−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.
And knocking down Egr1 in Cdk6−/− BCR-ABLp210+ LSCs enhanced the cells’ ability to form colonies.
The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”
