ABSTRACT
Genes of the MAGE family are expressed in several types of solid tumors and hematological malignancies but are silent in normal tissues. Therefore. Peptides encoded by MAGE genes are strictly tumor-specific antigens and constitute promising targets for immunotherapy. Identification of immunogenic leukemia-associated antigens as target structures is mandatory for specific immunotherapy of leukemia. Immunotherapy is promising to improve the prognosis of human leukemias, at least as adjuvant treatment, and tumor-associated antigens such as antigens encoded by MAGE genes might provide tools in this field. The expression of 3 genes of the MAGE family: MAGE-Al, MAGE-B2, and MAGE-A3, was tested with reverse transcriptase polymerase chain reaction [RT-PCR] in 10 healthy subjects, and in 45 leukemia patients; 15 acute myelogenous leukemia [AML], 15 acute lymphoblastic leukemia [ALL], and 15 chronic myelogenous leukemia [CML] samples. Healthy subjects were negative for the MAGE genes tested. Among 45 leukemias from various subtypes, 5/15 [33.3%] AML were positive for one of the three genes analyzed as follows [MAGE-Al 3/15; MAGE-B2 2/15; MAGE-A3 0/15]. Expression was also detected in 4/15 [26.7%] ALL patients [MAGE-A1 0/15; MAGE-B2 4/15; MAGE-A3 0/15]. Patients with CML showed one patient positive for MAGE-B2 [1/15, 6.7%]. The use of specific immunotherapy as an alternative or adjuvant treatment for leukemia requires the identification of immunogenic leukemia-associated antigens. Human tumor-specific antigens consisting of peptides presented by class 1 human leucocyte antigens [HLAs] to autologous cytolytic T lymphocytes [CTLs] have been identified, and may constitute targets for specific immunotherapy. Leukemia-associated antigens such as proteins encoded by MAGE genes might provide tools for immunotherapy of leukemia. Positive and negative results of MAGE gene expression in hematological malignancies have been reported. This led us to study MAGE gene expression in human leukemias using RT-PCR. MAGE genes may provide safe targets for specific immunotherapy, because they are silent in normal tissues. Because the pattern of expression of these genes results in the presence of antigens on many tumors of various histological types and not on normal tissues, these antigens qualify for cancer immunotherapy. It was demonstrated recently that the presentation peptides encoded by MAGE genes might make leukemic blasts suitable targets to CTLs, and because of this tumor-specific expression. MAGE genes ought to encode antigens that could be useful for antitumoral therapeutic vaccination
Subject(s)
Humans , Leukemia , Antigens, Neoplasm , Acute Disease , Immunotherapy , Chronic Disease , RNA, MessengerABSTRACT
The lack of a cancer cure results in the increasing number of drugs in development to treat cancer. Progress toward highly targeted drugs will increase significantly in the next years, as there are more drugs that apply new science and target difficult-to-treat forms of cancer. There is a strong need that the new cancer treatments continue to improve, to become more targeted and less toxic medicines. From and understanding of the core components of the apoptosis machinery at the molecular and structural levels, many potential new therapies for leukemia and lymphoma are emerging. Livin, a member of the inhibitor of apoptosis proteins [IAPs], has been considered to be a poor prognostic marker in malignancies, however, little is known about the clinical relevance of Livin expression in acute lymphoblastic leukemia [ALL]. In this study, the expression of Livin was analyzed in 10 normal healthy controls and 37 patients with de novo acute lymphoblastic leukemia [ALL]; 23 males and 14 females; 13 children and 24 adults; 19 B-lineage, 15 T-lineage, and 3 undifferentiated; 28 with TLC below 50.000/ul and 9 with TLC exceeding 50.000/ul; 30 with BM blast infiltration exceeding 90% and 7 below total infiltration. Diagnosis of ALL was based on morphological, cytochemical and immunophenotyping criteria, and Livin expression was analyzed using a Real-Time Quantitative Reverse-Transcriptase Polymerase Chain Reaction [RTO-PCR] to investigate a possible association or correlation with the clinical features at diagnosis, such as sex, age, lineage, HB, TLC, platelets and BM infiltration. Living was higherly expressed in all the 37 ALL studied patients, i.e., [100%]. Both Living expression rates and expression levels were statistically significantly higher in All patients than in controls [p<0.001], with no statistically significant differences, associations or correlations between Livin expression rates and expression levels and any of the above clinical data [P>0.05]. The death mechanism by which mammalian cells maintain homeostasis is apoptosis. Defects in the apoptotic pathway lead to expansion of cancer and affect the ability to respond to therapy. The inhibitor of apoptosis proteins [IAPs] family has become increasingly prominent in the field of cancer and aberrant expression or function of IAPs have been implied to be involved in the pathogenesis and progression of human cancer. Pathological over-expression of IAPs has been documented in cancer and leukemia, and the functional importance of IAPs for apoptosis supression in cancers has been documented by antisense experiments. Livin is an IAP family member, which is expressed at high levels preferentially in human carcinomas. Livin-specific antisense oligonucleotides were developed for modulation of Livin expression and for treatment of diseases associated with aberrant expression of Livin. Many studies suggest that Livin expression is a novel prognostic marker in ALL and thus needs to be incorporated into the patient stratification and treatment protocols. In addition, a quarter of ALL patients fail therapy and novel treatments that are focused on undermining specifically the leukemic process are needed urgently