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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-06-1668.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 202-209
IMMUNOBIOLOGY
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, and
Giovanni Battista Ferrara
From the Laboratory of Immunogenetics and Laboratory of
Molecular Morphogenesis, National Cancer Research Institute, Advanced
Biotechnology Center, Genoa, Italy; Department of
Oncology, Biology and Genetics, University of Genoa,
Italy; Service of Transfusion Medicine, S Orsola-Malpighi
Hospital, Bologna, Italy; Department of Internal Medicine,
University of Genoa, Italy; Department of Experimental
Pathology, University of Bologna, Italy; Institute of
Hematology and Clinical Oncology L & A Seragnoli,
Hemolymphopathology Section, University of Bologna,
Italy; Department of Pediatrics, University of Padua
Medical School, Italy.
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 AML based on CTLA-4 targeting.
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