MIUR: FIRB2001 – RBAU01RLNB_008, 2004-2006: “Signal transduction inhibitors as therapeutic molecules for Ph1+ leukemia”
Project Objectives
The project aims to test the immunogenicity of alternative peptide antigens, generated during the fusion of two genes, ABL and BCR, which characterizes all Ph-positive leukemia, especially those affecting adult individuals. This research group has extensively analyzed these genes over the years (Haematology. 86 (3): 252-9, 2001). The molecular alteration characterizing chronic myeloid leukemia, resulting from the translocation that generates the Philadelphia chromosome, is represented by the formation of a hybrid BCR/ABL gene, which results in the constitutive activation of tyrosine kinase activity in the ABL gene (Blood. 95 (12): 4019-20, 2000).
The therapeutic objective of CML and other Ph-positive leukemia is the achievement and maintenance of minimal residual disease or complete molecular remission, according to a value below the sensitivity threshold of the most commonly used PCR techniques (PCR negativity). During these years, several studies have clearly demonstrated that in certain cases, the control of the re-expansion of the leukemic clone (and sometimes its complete eradication) probably occurs through an immune mechanism. Therefore, it was hypothesized that leukemic cells can express antigens capable of stimulating the immune system even in an autologous condition and that these antigens are different from those expressed by normal cells.
Many approaches aimed to assess the possibility of triggering or stimulating an immune response against leukemia and lymphoma cells have used different immunotherapeutic procedures targeted against potential antigens, specific to leukemia cells. Some researchers have hypothesized the use of peptide antigens derived from the junction point of hybrid proteins (such as BCR-ABL proteins, which characterize all Ph-positive leukemia) because of their potential immunogenicity related to their absence in normal cells.
These potential antigens can act as such only if they are presented in association with class I molecules of the HLA system and thus for their affinity for the different alleles that constitute this system and which can vary from case to case. If so, the presence of some HLA genotypes could be protective against the onset of the disease. Accordingly, in some cases, the study of the distribution of HLA genotypes in populations of leukemia patients showed a different frequency rate of certain genotypes compared to that found in control populations.
In addition to the main hybrid transcripts, which are the majority, secondary transcripts are also often found, which derive from alternative splicing between the exons of the genes that are involved in the rearrangement process (Br J Haematol. 111 (2): 644-6, 2000 ). Proteins derived from these hybrid transcripts are richly conserved in different patients and contain amino acid sequences that are not present in normal cells. Hence, these proteins can be potentially exploited as antigens specific for leukemia and lymphoma cells, in order to develop therapeutic approaches targeted to induce or stimulate a specific anti-tumor response.
Our recent studies have actually reported the presence of hybrid transcripts deriving from alternative splicing between BCR and ABL genes in patients affected by chronic myeloid leukemia and other Ph-positive leukemia. In some of these transcripts, the junction between the BCR and ABL exons is such as to cause the frameshift of ABL reading frame sequences, potentially leading to proteins composed by fragments of the BCR gene fused to 6 or 8 amino acids, deriving from the frameshift of the reading frame of ABL second exon.
Start/End Date
January 23, 2004 - January 23, 2007
Principal Investigator
Prof. Vito Michele Fazio
Host Institution
Università degli Studi di Bologna
Other Institutions involved
- Università degli Studi di Siena
- Istituto Nazionale per lo studio e la cura dei Tumori
- Università degli Studi di Genova
- Università degli Studi di Udine
- Sapienza Università degli Studi di Roma
- Università degli Studi di Napoli Federico II
Source of funding
Italian Ministry of Health