title: 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+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ 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+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta 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+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid 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.
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Diaz-Blanco
authors.forename: I
authors.initials: I
authors.lastname: Bruns
authors.forename: F
authors.initials: F
authors.lastname: Neumann
authors.forename: J C
authors.initials: JC
authors.lastname: Fischer
authors.forename: T
authors.initials: T
authors.lastname: Graef
authors.forename: M
authors.initials: M
authors.lastname: Rosskopf
authors.forename: B
authors.initials: B
authors.lastname: Brors
authors.forename: S
authors.initials: S
authors.lastname: Pechtel
authors.forename: S
authors.initials: S
authors.lastname: Bork
authors.forename: A
authors.initials: A
authors.lastname: Koch
authors.forename: A
authors.initials: A
authors.lastname: Baer
authors.forename: U-P
authors.initials: UP
authors.lastname: Rohr
authors.forename: G
authors.initials: G
authors.lastname: Kobbe
authors.forename: A
authors.initials: A
authors.lastname: von Haeseler
authors.forename: N
authors.initials: N
authors.lastname: Gattermann
authors.forename: R
authors.initials: R
authors.lastname: Haas
authors.forename: R
authors.initials: R
authors.lastname: Kronenwett
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000737:chemistry*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000235:genetics; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D054411:Receptors, Leptin; D016044:Fusion Proteins, bcr-abl