Hematopoietic stem cells (HSC) are able to self-renew and give rise to all the blood cell types. Almost all of self-renewing HSC are so-call long-term (LT-HSC), which are capable of reconstituting lethaly-irradiated mice for a long time, unlike short-term HSC, which keep mice alive for the first 2-3 months and give a lot of progenitors. Most LT-HSC are non- or very slow-dividing cells and reside within bone marrow niches in a dormant condition. The ability to maintain this non-dividing condition, or in other terms, stay in the G-0 phase of cell cycle, is called quiescence.

Scheme of cell cycle phases and place of quiescence:

Because it has been proposed that cancer stem cells (CSC) have the same qualities as normal stem cells, the vast majority of them also should stay quiescent and able to self-renew. Because majority of anti-cancer drugs target actively-dividing (cycling) cells, quiescent CSC stayed alive and caused relapses and progression of disease. It would be cool to target CSC precisely based on their unique qualities and eradicate cancer. Quiescence could be the new potential target for anticancer therapy.

Now, according to a recent international study, published online in Nature journal, we can get a solution for targeting quiescence of CSC.

The authors describe a gene - PML, which regulates HSC function through maintenance of quiescence. When researchers serially transplanted bone marrow cells with leukemic oncogene, cells from mice with lack of PML were not able to generate leukemia on 3rd round because the self-renewal and quiescence of leukemia-initiating cells (LIC) were impaired.

Based on these results, the authors used the well-known anti-leukemic drug arsenic trioxide, which selectively and reversibly decreases PML expression on HSC and causes their impaired quiescence. This drug had a remarkable inhibitory effect on LIC maintanance. Arsenic trioxide-induced cycling increased LIC-killing effect of another anti-leukemic drug - Ara-C, which induces apoptosis of dividing cells. The combination of both drugs was able to inhibit leukemogenesis in secondary BMT unlike Ara-C treatment only. Even more, only by combining these two drugs leads to complete cure (ei LIC eradication) of disease in half of recipient mice.

I’d like to pointed out few important conclusions which came up and are confirmed in this study:
* There is a concept that quiescence of CSC may be one of the mechanisms underlying their chemoresistance;
* We can eliminate quiescent LIC for treatment through manipulation of genes-regulators of normal HSC function. Seems like we have only one tool for playing with quiescence so far - to induce cells to enter cell cycle;
* What happened with normal HSC? They also should be affected by these drugs. The answer is that - YES, normal HSC are also affected, but as the authors show, LIC are more sensitive to induction of cell cycle entry by arsenic trioxide, and the amount of quiescent HSC is quite enough to sustain normal hematopoiesis.
* Authors showed exactly the same effect of arsenic trioxide on LIC and HSC (through downregulation of PML) for human chronic myeloid leukemia compared with normal volunteer samples. So, this study could be considered like a preclinical one and arsenic trioxide could be recommended as a component of complex antil-leukemic chemotherapy, targeted towards quiescent leukemia-initiating cells.

————————
Nature AOP 11 May 2008; doi:10.1038/nature07016
picture credit