by Monya Baker
The cell cycle inhibitor p21 gives cancer cells the chance to repair DNA
To sustain disease, leukemia stem cells have to keep on dividing. To do so cells require a counterintuitive resource: a protein that keeps cells from proliferating. Work reported in Nature this month shows that, by giving cancer stem cells a chance to slow down and repair DNA damage, the protein p21, a cell-cycle inhibitor, not only helps cancer maintain itself, it helps leukemia evade therapies designed to kill rapidly dividing cells. Drugs that inhibit p21 or DNA repair, then, might help leukemia speed up and self destruct.
Pier Giuseppe Pelicci and colleagues at the University of Milano in Italy used different strains of genetically engineered mice to learn how leukemia sustains itself. One strain could not make p21 (a cyclin-dependent kinase inhibitor, also called p21Cip1 and Waf1). Another strain expressed the human version of the gene believed to initiate acute promyelocytic leukaemia. It codes for a fusion protein called PML-RAR. Both types of mice produced hematopoeitic stem (HS) cells that were comparable to HS cells from wild-type mice at proliferating in culture and engrafting into the bone-marrow of recipient mice. However, HSCs from mice with either genetic modification produced only a fourth to a sixth as many cells in engraftment and culture experiments, and mice that could not express p21 also did not develop full-fledged leukemia.
Further studies showed that PML-RAR initiated DNA damage in stem cells. It also upregulated p21, which stalled cell division long enough for cells to repair the DNA damage. The researchers looked for this response in fibroblasts and blood progenitor cells and found that, though DNA damage did occur and p21 was upregulated, p21's effects on cells' ability to proliferate were specific to stem cells. Next, the researchers examined the effects of another leukaemia oncogene (AML1-ETO) along with p21. While 10 of 17 mice that expressed both the oncogene and p21 developed leukemia, no leukemia was observed in 17 mice expressing the oncogene but not p21.
This is the first demonstration that a cell-cycle inhibitor is required to launch leukemia and sustain it. Interestingly, p21 does not actually transform cells to a cancerous state, but rather permits the dangerous cells to accumulate and proliferate. The work suggests that targeting p21 itself as well as preventing DNA repair could be useful strategies to treat leukemia.
Source: Nature