Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to imatinib.
Blood, 2009/12/10;114(25):5191-200.
Lemoli RM[1], Salvestrini V, Bianchi E, Bertolini F, Fogli M, Amabile M, Tafuri A, Salati S, Zini R, Testoni N, Rabascio C, Rossi L, Martin-Padura I, Castagnetti F, Marighetti P, Martinelli G, Baccarani M, Ferrari S, Manfredini R
Affiliations
PMID: 19855080DOI: 10.1182/blood-2008-08-176016
Impact factor: 25.476
Abstract
We show the molecular and functional characterization of a novel population of lineage-negative CD34-negative (Lin(-)CD34(-)) hematopoietic stem cells from chronic myelogenous leukemia (CML) patients at diagnosis. Molecular karyotyping and quantitative analysis of BCR-ABL transcript demonstrated that approximately one-third of CD34(-) cells are leukemic. CML Lin(-)CD34(-) cells showed kinetic quiescence and limited clonogenic capacity. However, stroma-dependent cultures induced CD34 expression on some cells and cell cycling, and increased clonogenic activity and expression of BCR-ABL transcript. Lin(-)CD34(-) cells showed hematopoietic cell engraftment rate in 2 immunodeficient mouse strains similar to Lin-CD34(+) cells, whereas endothelial cell engraftment was significantly higher. Gene expression profiling revealed the down-regulation of cell-cycle arrest genes and genes involved in antigen presentation and processing, while the expression of genes related to tumor progression, such as angiogenic factors, was strongly up-regulated compared with normal counterparts. Phenotypic analysis confirmed the significant down-regulation of HLA class I and II molecules in CML Lin(-)CD34(-) cells. Imatinib mesylate did not reduce fusion transcript levels, BCR-ABL kinase activity, and clonogenic efficiency of CML Lin(-)CD34(-) cells in vitro. Moreover, leukemic CD34(-) cells survived exposure to BCR-ABL inhibitors in vivo. Thus, we identified a novel CD34(-) leukemic stem cell subset in CML with peculiar molecular and functional characteristics.
MeSH terms
Animals; Antigens, CD34; Antineoplastic Agents; Benzamides; Bone Marrow Cells; Cells, Cultured; Cluster Analysis; Drug Resistance, Neoplasm; Flow Cytometry; Fusion Proteins, bcr-abl; Gene Expression Profiling; Humans; Imatinib Mesylate; Interleukin Receptor Common gamma Subunit; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Piperazines; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; Transplantation, Heterologous; beta 2-Microglobulin
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