Regulation of leukemic stem cells self-renewal and quiescence – the role of p21

by on February 8, 2009 · 1 comment

in cancer stem cell, leukemia, quiescence

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Blogging on Peer-Reviewed ResearchA new study published in Nature indicated that a well-known cyclin-dependent inhibitor (CDI), p21 can actually protect the leukemic stem cell pool through limiting DNA damage, keeping them in a quiescent state and carrying through hematopoietic stem cell self-renewal.

A search for “p21” in PubMed, gave me 1440 papers so far. Most of those papers demonstrate the tumor proliferation inhibition effect of this molecule, which can restrain cells from proceeding to the G1 phase. Numerous studies even try to over-express p21 as one cancer gene therapy strategy.

Italian group (Pier Giuseppe Pelicci and colleagues at the University of Milano) used the oncogene PML-RAR model, which is well known in initiating human acute promyelocytic leukemia (APL), to investigate the role of p21 in the regulation of leukemic stem cells. In order to do that they back crossed PML-RAR knock-in mice and WT or p21-/- mice. Surprisingly, after serial transplantation, PML/RAR+p21-/- HSC showed decreased self-renewal ability. Interestingly, p21 can be up-regulated by DNA damage or other types of environmental stress. PML-RAR fusion can up-regulate p21, notably, especially in the stem cell compartment and keep the cells quiescent. So, p21 can protect those HSCs from DNA damage and induce their cell cycle restriction. These effects appears not only in PML-RAR induced APL, but also in AML1-ETO (another fusion oncogene) induced acute myelogenous leukemia.

This study left several questions open for us. We have to re-evaluate cancer chemotherapy strategies which try to up-regulate cell cycle arrest genes or down-regulate cell cycle promoting genes. The hope for a cure for cancer seems dependent on the complete depletion of both oncogenes, which maintain differentiated cancer cell survival, and cancer stem cells, which are capable of repopulating the whole tumor colony. To eliminate cancer stem cells, we can either wake up these cells from their dormancy or increase their self-damage.

One natural question is whether p21 is the only CDI to limit DNA damage and maintain leukemia stem cell self-renewal and quiescence. The other question is how is p21 regulated in cancer stem cells? According to previous reports, p21 is a down-stream target of p53 – a very well known tumor-supressor. If p53 is functionally/physically mutated or deleted in the cancer stem cell, could p21 also get affected?

Actually, if we trace back to 4 years ago, a study showed BCR-ABL expression in a hematopoietic cell line increased p21expression, which is consistent with the current paper. A followup study showed dual function of p21 to BCR-ABL induced chronic meylogenous leukemia (CML). p21 deletion can both enhance CML proliferation and apoptosis induced by anti-leukemic drugs (imatinib and taxol). Isn’t it a flashing light that oncogene expression can increase CDI expression? Maybe a huge discovery is just around the corner? To me, it’s a hint to find out the key mechanism involved in the de-differentiation that occurs during oncogenesis.

Nature 2009;457:51

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also read:

Stalling cell division keeps leukaemia stem cells going (Nature Reports Stem Cells)
Stem Cells, Quiescence and Cancer (Hematopoiesis)
Mapping quiescence of hematopoietic stem cells (Hematopoiesis)

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