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 Export

@article{citeulike:6057755, 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 about 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, cell cycling, increased clonogenic activity and expression of BCR-ABL transcript. Lin-CD34- cells showed hematopoietic cell engraftment rate in two 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, genes involved in antigen presentation and processing, while the expression of genes related to tumor progression, such as angiogenic factors, was strongly up-regulated when compared to 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. 10.1182/blood-2008-08-176016}, author = {Lemoli, Roberto M. and Salvestrini, Valentina and Bianchi, Elisa and Bertolini, Francesco and Fogli, Miriam and Amabile, Marilina and Tafuri, Agostino and Salati, Simona and Zini, Roberta and Testoni, Nicoletta and Rabascio, Cristina and Rossi, Lara and Martin-Padura, Ines and Castagnetti, Fausto and Marighetti, Paola and Martinelli, Giovanni and Baccarani, Michele and Ferrari, Sergio and Manfredini, Rossella}, citeulike-article-id = {6057755}, citeulike-linkout-0 = {http://dx.doi.org/10.1182/blood-2008-08-176016}, citeulike-linkout-1 = {http://bloodjournal.hematologylibrary.org/content/blood-2008-08-176016v1/.abstract}, citeulike-linkout-2 = {http://bloodjournal.hematologylibrary.org/content/blood-2008-08-176016v1/.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19855080}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19855080}, day = {23}, doi = {10.1182/blood-2008-08-176016}, journal = {Blood}, keywords = {leukemia, resistance, stem-cell}, month = {October}, pages = {blood-2008-08-176016+}, posted-at = {2009-11-03 00:40:34}, priority = {2}, title = {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}, url = {http://dx.doi.org/10.1182/blood-2008-08-176016}, year = {2009} }

TY - JOUR ID - citeulike:6057755 L3 - citeulike-article-id:6057755 N2 - 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 about 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, cell cycling, increased clonogenic activity and expression of BCR-ABL transcript. Lin-CD34- cells showed hematopoietic cell engraftment rate in two 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, genes involved in antigen presentation and processing, while the expression of genes related to tumor progression, such as angiogenic factors, was strongly up-regulated when compared to 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. 10.1182/blood-2008-08-176016 JF - Blood TI - 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 SP - blood-2008-08-176016 KW - leukemia KW - resistance KW - stem-cell AU - Lemoli, Roberto AU - Salvestrini, Valentina AU - Bianchi, Elisa AU - Bertolini, Francesco AU - Fogli, Miriam AU - Amabile, Marilina AU - Tafuri, Agostino AU - Salati, Simona AU - Zini, Roberta AU - Testoni, Nicoletta AU - Rabascio, Cristina AU - Rossi, Lara AU - Martin-Padura, Ines AU - Castagnetti, Fausto AU - Marighetti, Paola AU - Martinelli, Giovanni AU - Baccarani, Michele AU - Ferrari, Sergio AU - Manfredini, Rossella PY - 2009/10/23/ UR - http://dx.doi.org/10.1182/blood-2008-08-176016 ER -