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, stromadependent 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.
| Original language | English |
|---|---|
| Pages (from-to) | 5191-5200 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 114 |
| Issue number | 25 |
| DOIs | |
| Publication status | Published - Dec 10 2009 |
Fingerprint
ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
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. / Lemoli, Roberto M.; Salvestrini, Valentina; Bianchi, Elisa; Bertolini, Francesco; Fogli, Miriam; Amabile, Marilina; Tafuri, Agostino; Salati, Simona; Zini, Roberta; Testoni, Nicoletta; Rabascio, Cristina; Rossi, Lara; Martin-Padura, Ines; Castagnetti, Fausto; Marighetti, Paola; Martinelli, Giovanni; Baccarani, Michele; Ferrari, Sergio; Manfredini, Rossella.
In: Blood, Vol. 114, No. 25, 10.12.2009, p. 5191-5200.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Lemoli, Roberto M.
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 - 2009/12/10
Y1 - 2009/12/10
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 approximately one-third of CD34- cells are leukemic. CML Lin-CD34- cells showed kinetic quiescence and limited clonogenic capacity. However, stromadependent 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.
AB - 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, stromadependent 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.
UR - http://www.scopus.com/inward/record.url?scp=73949142609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73949142609&partnerID=8YFLogxK
U2 - 10.1182/blood-2008-08-176016
DO - 10.1182/blood-2008-08-176016
M3 - Article
VL - 114
SP - 5191
EP - 5200
JO - Blood
JF - Blood
SN - 0006-4971
IS - 25
ER -