CTLA-4 expressed by chemoresistant, as well as untreated, myeloid leukaemia cells can be targeted with ligands to induce apoptosis

Stefania Laurent, Giulio L. Palmisano, Alberto M. Martelli, Tomohiro Kato, Pier Luigi Tazzari, Ivana Pierri, Marino Clavio, Beatrice Dozin, Giuseppe Balbi, Mauro Megna, Anna Morabito, Teresa Lamparelli, Andrea Bacigalupo, Marco Gobbi, Maria Pia Pistillo

Research output: Contribution to journalArticle

Abstract

We have previously reported that about 80% of acute myeloid leukaemia (AML) samples tested at diagnosis constitutively expressed cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). The present study compared CTLA-4 expression and function of leukaemic cells from AML patients at diagnosis with those from AML patients resistant to conventional chemotherapy. We also explored the possibility of targeting CTLA-4 for apoptosis induction in chemoresistant AML cells. AML cells either from untreated patients (n = 15) or in chemoresistant phase (n = 10) were analysed for CTLA-4 protein and transcript expression by flow cytometry and reverse transcription-polymerase chain reaction respectively. CTLA-4 expression was similar in untreated and in chemoresistant samples and was not associated with patients' clinical features. In chemoresistant AML cells, CTLA-4 transduced an apoptotic signal on engagement with its recombinant ligands r-CD80 and r-CD86, which induced an average of 71% and 62% apoptotic cells, respectively, at highest concentration. Apoptosis was equally induced in untreated leukaemic cells accompanied by cleavage of procaspase-8 and -3. Thus, this study provides the first evidence that killing of leukaemic cells from AML patients may be obtained by the engagement of CTLA-4 with its ligands, opening the way to a novel potential therapeutic approach based on triggering the CTLA-4 molecule to circumvent chemoresistance in AML.

Original languageEnglish
Pages (from-to)597-608
Number of pages12
JournalBritish Journal of Haematology
Volume136
Issue number4
DOIs
Publication statusPublished - Feb 2007

Keywords

  • Acute myeloid leukaemia
  • Apoptosis
  • Chemoresistance
  • Cytotoxic T-lymphocyte-associated antigen-4
  • Ligands

ASJC Scopus subject areas

  • Hematology

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