Chemosensitization of AML

Another nail in the AML coffin by Camille N Abboud, Blood 2009(Jun 11); 113(24): 6045-6. Editorial [Full text is currently publicly accessible][PubMed Citation]. First paragraph:

In this issue of Blood, Nervi and colleagues and Zeng and colleagues independently report similar findings in both in vitro and in vivo AML models, showing chemosensitization by blocking CXCR4/CXCL12 (SDF-1{alpha}:stromal cell–derived factor 1) signaling using novel CXCR4 antagonist bicyclams, namely AMD3100 (plerixafor) and AMD3465.

Excerpt from the final paragraph:

Finally, while both reports open new avenues for overcoming in vivo drug resistance in AML, it is yet unclear whether durable complete remissions can ensue from this strategy. AML is indeed a very heterogenous disease, and successful eradication of leukemic stem/progenitor cells will require blocking multiple receptors/pathways ...

The two articles discussed in this editorial are:

1) Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100 by Bruno Nervi and 10 co-authors, including Timothy J Ley, and John F DiPersio, Blood 2009(Jun 11); 113(24): 6206-14 [Epub 2008(Dec 2)]. [PubMed Citation].

2) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML by Zhihong Zeng and 12 co-authors, Blood 2009(Jun 11); 113(24): 6215-24 [Epub 2008(Oct 27)]. [PubMed Citation][FriendFeed entry].

[Only the abstracts of these two articles are currently publicly accessible].

CD133 is a marker of bioenergetic stress in human glioma

CD133 is a marker of bioenergetic stress in human glioma by Corinne E Griguer and 6 co-authors, including G Yancey Gillespie, PLoS ONE 2008; 3(11): e3655. Epub 2008 Nov 5. PubMed Abstract:

Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.

Excerpts from the Discussion section of the full text (openly accessible):

Figure 7. Tumor progression model

Last paragraph:

We described here that hypoxia and modification of the bioenergetic status of glioma cells govern the regulation of CD133 at post-transcriptional level. Data presented here strongly indicated that changes in the cellular environment that results in alteration of mitochondrial function are responsible for the enhanced up-regulation of CD133 antigen in glioma cells, suggesting that CD133 expression in human glioma cells is not obligatory relative to the stem cell phenotype but rather, reveals the occurrence of a stress response.