title: Alteration Analysis of Bone Marrow Mesenchymal Stromal Cells from De Novo Acute Myeloid Leukemia Patients at Diagnosis.
abstract: Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) frequently display alterations in several hematologic disorders, such as acute lymphoid leukemia, acute myeloid leukemia (AML), and myelodysplastic syndromes. In acute leukemias, it is not clear whether MSC alterations contribute to the development of the malignant clone or whether they are simply the effect of tumor expansion on the microenvironment. We extensively investigated the characteristics of MSCs isolated from the BM of patients with de novo AML at diagnosis (L-MSCs) in terms of phenotype (gene and protein expression, apoptosis and senescence levels, DNA double-strand break formation) and functions (proliferation and clonogenic potentials, normal and leukemic hematopoiesis-supporting activity). We found that L-MSCs show reduced proliferation capacity and increased apoptosis levels compared with MSCs from healthy controls. Longer population doubling time in L-MSCs was not related to the AML characteristics at diagnosis (French-American-British type, cytogenetics, or tumor burden), but was related to patient age and independently associated with poorer patient outcome, as was cytogenetic prognostic feature. Analyzing, among others, the expression of 93 genes, we found that proliferative deficiency of L-MSCs was associated with a perivascular feature at the expense of the osteo-chondroblastic lineage with lower expression of several niche factors, such as KITLG, THPO, and ANGPT1 genes, the cell adhesion molecule VCAM1, and the developmental/embryonic genes, BMI1 and DICER1. L-MSC proliferative capacity was correlated positively with CXCL12, THPO, and ANGPT1 expression and negatively with JAG1 expression. Anyway, these changes did not affect their in vitro capacity to support normal hematopoiesis and to modify leukemic cell behavior (protection from apoptosis and quiescence induction). Our findings indicate that BM-derived MSCs from patients with newly diagnosed AML display phenotypic and functional alterations such as proliferative deficiency that could be attributed to tumor progression, but does not seem to play a special role in the leukemic process.
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .
authors.forename: Laura
authors.initials: L
authors.lastname: Desbourdes
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .
authors.forename: Joaquim
authors.initials: J
authors.lastname: Javary
authors.affiliation: 2 Department of Biological Hematology, University Hospital of Tours , Tours, France .
authors.forename: Thomas
authors.initials: T
authors.lastname: Charbonnier
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .
authors.forename: Nicole
authors.initials: N
authors.lastname: Ishac
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .
authors.forename: Jerome
authors.initials: J
authors.lastname: Bourgeais
authors.affiliation: 2 Department of Biological Hematology, University Hospital of Tours , Tours, France .|3 Department of Hematology and Cell Therapy, University Hospital of Tours , Tours, France .
authors.forename: Aurore
authors.initials: A
authors.lastname: Iltis
authors.affiliation: 4 INSERM U935, University of Poitiers , Poitiers, France .|5 Department of Biological Oncology, University Hospital of Poitiers , Poitiers, France .
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Chomel
authors.affiliation: 6 INSERM U935, University of Paris-Sud 11 , Paris, France .|7 Department of Hematology, University Hospitals of Paris-Sud , Le Kremlin Bicêtre, France .
authors.forename: Ali
authors.initials: A
authors.lastname: Turhan
authors.affiliation: 8 INSERM U917, University of Rennes 1 , Rennes, France .
authors.forename: Fabien
authors.initials: F
authors.lastname: Guilloton
authors.affiliation: 8 INSERM U917, University of Rennes 1 , Rennes, France .|9 Department of Immunology, Cellular Therapy and Hematopoiesis, University Hospital of Rennes , Rennes, France .|10 CNRS GDR 3697, MicroNiT National Network, Tours , France .
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: 11 CNRS UMR 7292, Telomeres and Genome Stability Team, François Rabelais University , Tours, France .
authors.forename: Marie-Veronique
authors.initials: MV
authors.lastname: Demattei
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .
authors.forename: Elfi
authors.initials: E
authors.lastname: Ducrocq
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .
authors.forename: Florence
authors.initials: F
authors.lastname: Rouleux-Bonnin
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .|3 Department of Hematology and Cell Therapy, University Hospital of Tours , Tours, France .
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .|2 Department of Biological Hematology, University Hospital of Tours , Tours, France .|10 CNRS GDR 3697, MicroNiT National Network, Tours , France .
authors.forename: Olivier
authors.initials: O
authors.lastname: Hérault
authors.affiliation: 1 CNRS UMR 7292, LNOx Team, François Rabelais University , Tours, France .|2 Department of Biological Hematology, University Hospital of Tours , Tours, France .|10 CNRS GDR 3697, MicroNiT National Network, Tours , France .
authors.forename: Jorge
authors.initials: J
authors.lastname: Domenech
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D008875:Middle Aged; D010641:Phenotype; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor
keywords: acute myeloid leukemia; hematopoiesis; mesenchymal stromal cells; microenvironment; niche