CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells

Maria Pia Pistillo, Pier Luigi Tazzari, Giulio Lelio Palmisano, Ivana Pierri, Andrea Bolognesi, Francesca Ferlito, Paolo Capanni, Letizia Polito, Marina Ratta, Stefano Pileri, Milena Piccioli, Giuseppe Basso, Laura Rissotto, Roberto Conte, Marco Gobbi, Fiorenzo Stirpe, Giovanni Battista Ferrara

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Abstract

The expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) molecule in human normal and neoplastic hematopoietic cells, both on the cell membrane and in the intracellular compartment, was evaluated. Flow cytometric analysis carried out with a panel of anti-CTLA-4 human single-chain fragment of variable domain (scFv) antibodies revealed that CTLA-4 was not expressed on the surface, whereas it was highly expressed within the cytoplasm, in freshly isolated peripheral blood mononuclear cells (PBMCs), T cells, B cells, CD34+ stem cells, and granulocytes. Various treatments with agents able to specifically activate each cell type induced CTLA-4 expression on the surface of these cells. Similarly, increased CTLA-4 expression Was observed in different hematopoietic cell lines although they also expressed surface CTLA-4, at different degrees of intensity, before activation. Surprisingly, CTLA-4 RNA transcripts were detectable in such cell lines only after nested polymerase chain reaction (PCR) specific for CTLA-4 extracellular domain, suggesting a very fast CTLA-4 RNA processing accompanied by prolonged CTLA-4 protein accumulation. We further demonstrated surface expression of CTLA-4 in a variety of acute and chronic myeloid leukemias (AMLs and CMLs) and B- and T-lymphoid leukemias, either adult or pediatric. CTLA-4 was expressed in 25% to 85% of AMLs and CMLs depending on the leukemia subtype and the epitope analyzed, whereas in acute B-and T-leukemias CTLA-4 expression was mainly cytoplasmic. Chronic B leukemias appeared to express CTLA-4, both on the surface and in cytoplasm, whereas few cases tested of chronic T leukemias were negative. Two anti-CTLA-4 immunotoxins (scFvs-saporin) induced in vitro apoptosis of neoplastic cells from a representative AML, suggesting a novel immunotherapeutic approach to AM L based on CTLA-4 targeting.

Original languageEnglish
Pages (from-to)202-209
Number of pages8
JournalBlood
Volume101
Issue number1
DOIs
Publication statusPublished - Jan 1 2003

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CTLA-4 Antigen
Cell Lineage
Cells
Lymphocytes
Apoptosis
Molecules
Leukemia
Emitter coupled logic circuits
Cytoplasm
RNA
Lymphoid Leukemia
Immunotoxins
Cell Line
Single-Chain Antibodies
Pediatrics
T-cells

ASJC Scopus subject areas

  • Hematology

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CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells. / Pistillo, Maria Pia; Tazzari, Pier Luigi; Palmisano, Giulio Lelio; Pierri, Ivana; Bolognesi, Andrea; Ferlito, Francesca; Capanni, Paolo; Polito, Letizia; Ratta, Marina; Pileri, Stefano; Piccioli, Milena; Basso, Giuseppe; Rissotto, Laura; Conte, Roberto; Gobbi, Marco; Stirpe, Fiorenzo; Ferrara, Giovanni Battista.

In: Blood, Vol. 101, No. 1, 01.01.2003, p. 202-209.

Research output: Contribution to journalArticle

Pistillo, MP, Tazzari, PL, Palmisano, GL, Pierri, I, Bolognesi, A, Ferlito, F, Capanni, P, Polito, L, Ratta, M, Pileri, S, Piccioli, M, Basso, G, Rissotto, L, Conte, R, Gobbi, M, Stirpe, F & Ferrara, GB 2003, 'CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells', Blood, vol. 101, no. 1, pp. 202-209. https://doi.org/10.1182/blood-2002-06-1668
Pistillo, Maria Pia ; Tazzari, Pier Luigi ; Palmisano, Giulio Lelio ; Pierri, Ivana ; Bolognesi, Andrea ; Ferlito, Francesca ; Capanni, Paolo ; Polito, Letizia ; Ratta, Marina ; Pileri, Stefano ; Piccioli, Milena ; Basso, Giuseppe ; Rissotto, Laura ; Conte, Roberto ; Gobbi, Marco ; Stirpe, Fiorenzo ; Ferrara, Giovanni Battista. / CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells. In: Blood. 2003 ; Vol. 101, No. 1. pp. 202-209.
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abstract = "The expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) molecule in human normal and neoplastic hematopoietic cells, both on the cell membrane and in the intracellular compartment, was evaluated. Flow cytometric analysis carried out with a panel of anti-CTLA-4 human single-chain fragment of variable domain (scFv) antibodies revealed that CTLA-4 was not expressed on the surface, whereas it was highly expressed within the cytoplasm, in freshly isolated peripheral blood mononuclear cells (PBMCs), T cells, B cells, CD34+ stem cells, and granulocytes. Various treatments with agents able to specifically activate each cell type induced CTLA-4 expression on the surface of these cells. Similarly, increased CTLA-4 expression Was observed in different hematopoietic cell lines although they also expressed surface CTLA-4, at different degrees of intensity, before activation. Surprisingly, CTLA-4 RNA transcripts were detectable in such cell lines only after nested polymerase chain reaction (PCR) specific for CTLA-4 extracellular domain, suggesting a very fast CTLA-4 RNA processing accompanied by prolonged CTLA-4 protein accumulation. We further demonstrated surface expression of CTLA-4 in a variety of acute and chronic myeloid leukemias (AMLs and CMLs) and B- and T-lymphoid leukemias, either adult or pediatric. CTLA-4 was expressed in 25{\%} to 85{\%} of AMLs and CMLs depending on the leukemia subtype and the epitope analyzed, whereas in acute B-and T-leukemias CTLA-4 expression was mainly cytoplasmic. Chronic B leukemias appeared to express CTLA-4, both on the surface and in cytoplasm, whereas few cases tested of chronic T leukemias were negative. Two anti-CTLA-4 immunotoxins (scFvs-saporin) induced in vitro apoptosis of neoplastic cells from a representative AML, suggesting a novel immunotherapeutic approach to AM L based on CTLA-4 targeting.",
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AU - Pistillo, Maria Pia

AU - Tazzari, Pier Luigi

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AU - Pierri, Ivana

AU - Bolognesi, Andrea

AU - Ferlito, Francesca

AU - Capanni, Paolo

AU - Polito, Letizia

AU - Ratta, Marina

AU - Pileri, Stefano

AU - Piccioli, Milena

AU - Basso, Giuseppe

AU - Rissotto, Laura

AU - Conte, Roberto

AU - Gobbi, Marco

AU - Stirpe, Fiorenzo

AU - Ferrara, Giovanni Battista

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N2 - The expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) molecule in human normal and neoplastic hematopoietic cells, both on the cell membrane and in the intracellular compartment, was evaluated. Flow cytometric analysis carried out with a panel of anti-CTLA-4 human single-chain fragment of variable domain (scFv) antibodies revealed that CTLA-4 was not expressed on the surface, whereas it was highly expressed within the cytoplasm, in freshly isolated peripheral blood mononuclear cells (PBMCs), T cells, B cells, CD34+ stem cells, and granulocytes. Various treatments with agents able to specifically activate each cell type induced CTLA-4 expression on the surface of these cells. Similarly, increased CTLA-4 expression Was observed in different hematopoietic cell lines although they also expressed surface CTLA-4, at different degrees of intensity, before activation. Surprisingly, CTLA-4 RNA transcripts were detectable in such cell lines only after nested polymerase chain reaction (PCR) specific for CTLA-4 extracellular domain, suggesting a very fast CTLA-4 RNA processing accompanied by prolonged CTLA-4 protein accumulation. We further demonstrated surface expression of CTLA-4 in a variety of acute and chronic myeloid leukemias (AMLs and CMLs) and B- and T-lymphoid leukemias, either adult or pediatric. CTLA-4 was expressed in 25% to 85% of AMLs and CMLs depending on the leukemia subtype and the epitope analyzed, whereas in acute B-and T-leukemias CTLA-4 expression was mainly cytoplasmic. Chronic B leukemias appeared to express CTLA-4, both on the surface and in cytoplasm, whereas few cases tested of chronic T leukemias were negative. Two anti-CTLA-4 immunotoxins (scFvs-saporin) induced in vitro apoptosis of neoplastic cells from a representative AML, suggesting a novel immunotherapeutic approach to AM L based on CTLA-4 targeting.

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