Subject(s)
Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , WT1 Proteins/biosynthesis , Adolescent , Adult , Aged , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Neoplasm, Residual , Risk Assessment , Risk Factors , Spain/epidemiology , WT1 Proteins/geneticsSubject(s)
Primary Myelofibrosis , Registries , Thrombocytopenia , Aged , Disease-Free Survival , Female , Humans , Male , Middle Aged , Primary Myelofibrosis/blood , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/mortality , Primary Myelofibrosis/therapy , Spain/epidemiology , Survival Rate , Thrombocytopenia/blood , Thrombocytopenia/diagnosis , Thrombocytopenia/mortality , Thrombocytopenia/therapyABSTRACT
Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution.
Subject(s)
Leukemia, Myeloid, Acute/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Adult , Aged , Bone Marrow Cells/cytology , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Differentiation , Cell Proliferation/drug effects , Cells, Cultured , Cytogenetic Analysis , Cytokines/metabolism , Female , Humans , Immunosuppression Therapy , In Situ Hybridization, Fluorescence , Interleukin-10/metabolism , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Mesenchymal Stem Cells/metabolism , Middle Aged , Phytohemagglutinins/pharmacology , Prognosis , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Aplastic anemia is a life-threatening bone marrow failure disorder characterized by peripheral pancytopenia and marrow hypoplasia. The majority of cases of aplastic anemia remain idiopathic, although hematopoietic stem cell deficiency and impaired immune responses are hallmarks underlying the bone marrow failure in this condition. Mesenchymal stem/stromal cells constitute an essential component of the bone marrow hematopoietic microenvironment because of their immunomodulatory properties and their ability to support hematopoiesis, and they have been involved in the pathogenesis of several hematologic malignancies. We investigated whether bone marrow mesenchymal stem cells contribute, directly or indirectly, to the pathogenesis of aplastic anemia. We found that mesenchymal stem cell cultures can be established from the bone marrow of aplastic anemia patients and display the same phenotype and differentiation potential as their counterparts from normal bone marrow. Mesenchymal stem cells from aplastic anemia patients support the in vitro homeostasis and the in vivo repopulating function of CD34(+) cells, and maintain their immunosuppressive and anti-inflammatory properties. These data demonstrate that bone marrow mesenchymal stem cells from patients with aplastic anemia do not have impaired functional and immunological properties, suggesting that they do not contribute to the pathogenesis of the disease.
