BCR/ABLp210, p190 and p230 fusion genes in 250 Mexican patients with chronic myeloid leukaemia (CML)

Abstract

There are two major forms of the BCR/ABL fusion gene, involving ABL exon 2, but including different exons of BCR gene. The transcripts b2a2 or b3a2 code for a p210 protein. Another fusion gene leads to the expression of an e1a2 transcript, which codes for a p190 protein. Another, less common fusion gene is c3a2[e19a2], which encodes a p230 protein. The incidence of one or the other rearrangement in chronic myeloid leukaemia (CML) patients varies in different reported series. This study was designed to determine the frequency of coexpresion of the p210, p190 and p230 transcripts in 250 Mexican patients with CML. We performed nested and multiplex reverse transcriptase polymerase chain reaction (RT-PCR) on bone marrow samples from adult patients and found that all cases were positive for some type of BCR/ABL rearrangement. In 226 (90.4%) patients it was p210, while the remaining 9.6% showed coexpression or one of the transcripts of p190/p210/p230. In 7% of patients with p210 expression there are both isoforms (b3a2/b2a2), presumably the result of alternative splicing. The rate of coexpression of the p190/p210 transcripts was 5%, which is much lower than in other reports. This may be due to the technical factors. These patients had high platelet counts, marked splenomegaly and chromosomal abnormalities in addition to Ph'. Other types of coexpression seen were p210/p230 and p190/p210/p230, in patients with high-risk clinical factors. Our study confirms the occurrence of coexpression of different BCR/ABL transcripts, although the rate (9.6%) was much lower than has been reported in other populations. This may reflect either the sensitivity of the detection techniques used or the possibility of genetic differences between the populations studied. Coexpression may be due to alternative splicing or to phenotypic variation, with clinical courses different from classical CML.

Amiloride Modulates Alternative Splicing in Leukemic Cells and Resensitizes Bcr-AblT315I Mutant Cells to Imatinib

“…Amiloride also exerts an effect on the splicing of the BCR/ABL tyrosine kinase oncogene, which results from a reciprocal translocation of chromosomes 9 and 22 in a hematopoietic stem cell (34). This chimeric oncoprotein, containing a constitutively activated tyrosine kinase domain, plays the key role in malignant transformation and triggers CML (35,36). Therefore, through the modulation of the alternative splicing of various apoptotic genes and BCR/ABL, amiloride may play a role in producing a proapoptosis phenotype with enhanced sensitization of cells to irradiation or chemotherapeutic drugs, initiating a new target for anticancer therapies.…”

Acute Lymphoblastic Leukemia Expressing b3a2 (p210), e1a2 (p190), and Variant e1a2 BCR-ABL Transcripts: A Case Report and Review of the Literature

“…In addition, e1a2 is present in 60–75% of patients with Ph-positive ALL [6,7] and only 1% of patients with CML [8]. In recent years, the e1a2 (p190) transcript has been constantly reported to coexist with b2a2 or b3a2 (p210) in patients with Ph-positive ALL and CML [5,9,10,11]. The coexpression of three or more types of fusion transcripts is occasionally reported only in CML patients [4,5].…”

“…At the genomic level, three different breakpoint cluster regions in the BCR gene (M- bcr , m- bcr , and µ- bcr ) have been reported [1], which generate commonly different transcripts and somewhat different proteins, b2a2 (p210), b3a2 (p210), e1a2 (p190), and c3a2 (p230) [3]. The b3a2 or b2a2 fusion transcripts are found in 83–90.4% of patients with CML [4,5]. In addition, e1a2 is present in 60–75% of patients with Ph-positive ALL [6,7] and only 1% of patients with CML [8].…”

“…In recent years, the e1a2 (p190) transcript has been constantly reported to coexist with b2a2 or b3a2 (p210) in patients with Ph-positive ALL and CML [5,9,10,11]. The coexpression of three or more types of fusion transcripts is occasionally reported only in CML patients [4,5]. In this study, a rare Ph-positive ALL patient who coexpresses b3a2 (p210), e1a2 (p190), and a novel variant of the e1a2 transcript is reported upon.…”

Philadelphia-Positive Acute Myeloblastic Leukemia: A Rare Entity

“…Minor BCR (m-BCR), e1a2 mRNA transcripts and p190 chimeric protein, are most frequently associated with Ph positive Acute lymphoblastic leukemia (ALL) and in many patients with CML. Third less common fusion gene involving breakpoint in micro BCR (µ-BCR), e19a2 and result in p230 chimeric protein, may demonstrate prominent neutrophilic leukocytosis; these should be diagnosed as chronic neutrophilic leukaemia [1,2].…”