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CTLA‐4 expressed by chemoresistant, as well as untreated, myeloid leukaemia cells can be targeted with ligands to induce apoptosis
Author(s) -
Laurent Stefania,
Palmisano Giulio L.,
Martelli Alberto M.,
Kato Tomohiro,
Tazzari Pier Luigi,
Pierri Ivana,
Clavio Marino,
Dozin Beatrice,
Balbi Giuseppe,
Megna Mauro,
Morabito Anna,
Lamparelli Teresa,
Bacigalupo Andrea,
Gobbi Marco,
Pistillo Maria Pia
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2006.06472.x
Subject(s) - cd86 , cd80 , apoptosis , cancer research , cytotoxic t cell , flow cytometry , cd33 , myeloid , immunology , medicine , biology , in vitro , t cell , immune system , cd34 , cd40 , microbiology and biotechnology , stem cell , biochemistry
Summary 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.