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. 2010 Jan 20;5(1):e8785.
doi: 10.1371/journal.pone.0008785.

Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells

E Camilla Forsberg  1 , Emmanuelle Passegué, Susan S Prohaska, Amy J Wagers, Martina Koeva, Joshua M Stuart, Irving L Weissman
Affiliations

Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells

E Camilla Forsberg et al. PLoS One. .

Abstract

Hematopoietic stem cells (HSC) are rare, multipotent cells capable of generating all specialized cells of the blood system. Appropriate regulation of HSC quiescence is thought to be crucial to maintain their lifelong function; however, the molecular pathways controlling stem cell quiescence remain poorly characterized. Likewise, the molecular events driving leukemogenesis remain elusive. In this study, we compare the gene expression profiles of steady-state bone marrow HSC to non-self-renewing multipotent progenitors; to HSC treated with mobilizing drugs that expand the HSC pool and induce egress from the marrow; and to leukemic HSC in a mouse model of chronic myelogenous leukemia. By intersecting the resulting lists of differentially regulated genes we identify a subset of molecules that are downregulated in all three circumstances, and thus may be particularly important for the maintenance and function of normal, quiescent HSC. These results identify potential key regulators of HSC and give insights into the clinically important processes of HSC mobilization for transplantation and leukemic development from cancer stem cells.

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Conflict of interest statement

Competing Interests: I.L.W. has stock in Amgen and is a cofounder of Cellerant Inc. and Stem Cells Inc. The other authors have no financial interests to disclose. There are no patents associated with this study.

Figures

Figure 1
Figure 1. Significance Analysis of Microarray (SAM) plots.
Pair-wise comparison of gene expression during HSC differentiation, mobilization, and leukemic transformation. Features colored green or red represent genes up- or downregulated, respectively, in each comparison.
Figure 2
Figure 2. Heatmap representation of differential gene expression.
Each of the 18 columns represents a pairwise comparison. Rows represent individual genes. Note that “nonLSC” and “nonMob” are the normal HSC counterparts to LSC and mobilized HSC.
Figure 3
Figure 3. Venn diagram representation of differential gene expression.
Lists of differentially expressed clones in each pairwise comparison were compared to identify clones that are shared or unique to different HSC fates. The numbers represent the number of up- or downregulated clones in each pairwise comparison and the number of clones shared between comparisons.
Figure 4
Figure 4. Quantitative RT-PCR of HSC, MPP, D+2 mobilized HSC and LSC.
The relative level of expression of genes identified by microarray analysis as downregulated upon HSC differentation, mobilization and leukemic transformation. Normal HSC levels were set to 100. Grey bars, HSC; red, MPP; blue, mobilized HSC; green, LSC.
Figure 5
Figure 5. Gene ontology classification of genes selectively expressed by normal, quiescent HSC.
Figure 6
Figure 6. Comparison between the findings in our study and six other reports on HSC gene expression.
The 93 genes selectively expressed in normal HSC are indicated in the left column. Additional columns represent the same 93 genes in each study, named below the respective column. Black indicates that the gene was upregulated in HSC; white indicates that the gene was not upregulated; gray indicates that the gene was not tested.
Figure 7
Figure 7. Putative transcription factor binding motifs enriched in upstream regulatory regions of genes selectively expressed by normal, quiescent HSC.
See this image and copyright information in PMC

References

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