Molecular signature of CD34+ hematopoietic stem and progenitor cells of patients with CML in chronic phase

Abstract

In this study, we provide a molecular signature of highly enriched CD34 þ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34 þ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34 þ cells were identified. These include upregulation of genes involved in the transforming growth factorb pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34 þ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34 þ cells showing an increase of the proportion of megakaryocyteerythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.

Insights into the stem cells of chronic myeloid leukemia

“…[115][116][117][118][119][120][121][122] These studies have also identified differentially expressed genes involved in the regulation of DNA repair, cell cycle control, cell adhesion, homing, transcription factors and drug metabolism. 117,[120][121][122][123] Potential new therapeutic targets include several recently identified regulators of CML stem and progenitor self-renewal and proliferation; for example, promyelocytic leukemia protein, b-catenin, various RNA binding proteins and members of the sonic hedgehog pathway. [89][90][91]97,124,125 Another candidate target identified is CXCR4, the chemokine receptor thought to be involved in normal stem cell localization in the marrow and found to promote the survival of quiescent CML progenitors.…”

A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes

“…miR-342 has been shown to stimulate granulocytic differentiation (De Marchis et al, 2009). Interestingly, the putative target of miR-342 MEIS1, a member of the TALE family of homeodomain Differentially expressed miRNAs in APL patients S Careccia et al genes, has been shown to have a pivotal role in normal hematopoiesis (Abramovich and Humphries, 2005;Diaz-Blanco et al, 2007) and it is frequently upregulated in human AMLs (Kumar et al, 2009). Finally, it is known the involvement of let-7 family members in differentiation and development, as well as in antiproliferative functions, by targeting the RAS oncogene and the non-histone DNA binding protein HMGA2 (Johnson et al, 2005;Peng et al, 2008).…”

The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence

“…3 Previously, we examined CD34 þ stem and progenitor cells from patients with chronic phase (CP) CML by microarray technology. 4 The gene expression profile of the total CD34 þ cell population was suggestive for an altered composition of the CD34 þ compartment and flow cytometry-based CD34 þ cell subset analysis showed a greater proportion of megakaryocyteerythrocyte progenitors (MEP) whereas HSC and GMP subsets were proportionally decreased. These observations prompted us to perform a more detailed analysis of the molecular signature of CP CML using defined subsets rather than the total population of CD34 þ stem and progenitor cells.…”