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

Roberto M. Lemoli, Valentina Salvestrini, Elisa Bianchi, Francesco Bertolini, Miriam Fogli, Marilina Amabile, Agostino Tafuri, Simona Salati, Roberta Zini, Nicoletta Testoni, Cristina Rabascio, Lara Rossi, Ines Martin-Padura, Fausto Castagnetti, Paola Marighetti, Giovanni Martinelli, Michele Baccarani, Sergio Ferrari, Rossella Manfredini

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)5191-5200
Number of pages10
JournalBlood
Volume114
Issue number25
DOIs
Publication statusPublished - Dec 10 2009

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Functional analysis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Stem cells
Stem Cells
Genes
Cells
Population
Angiogenesis Inducing Agents
Endothelial cells
Gene expression
Tumors
Phosphotransferases
Fusion reactions
Antigen Presentation
Antigens
Molecules
Kinetics
Processing
Chemical analysis
Down-Regulation

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 journalArticle

Lemoli, RM, 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 2009, '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, vol. 114, no. 25, pp. 5191-5200. https://doi.org/10.1182/blood-2008-08-176016
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. / 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. In: Blood. 2009 ; Vol. 114, No. 25. pp. 5191-5200.
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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.",
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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

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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.

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