Frequency of BCR/ABL Breakpoints in CML Venezuelan Patients : Contribution to a Possible Worldwide Distribution of BCR/ABL Transcripts Associated to Ethnicity

Abstract

Chronic myeloid leukemia (CML) is a common clinical pathology characterized by the clone expansion of stem cells of myeloid linage. At the cytogenetic and molecular level CML is associated with one reciprocal and nonrandom translocation (t(9;22)(q34;q11)) which causes the BCR/ABL gene fusion in the 22nd chromosome (Philadelphia chromosome, pH+). This gene codifies for a chimerical protein functionally active and able to exert a transforming effect on all the cells carrying that gene. The transcripts b2a2 and b3a2 are the principal variants identified on the CML patients. Due to high frequency and variation in expression of b2a2 and b3a2 transcripts in CML patients, the researchers have tried to associate the expression of those transcripts with clinical and ethnic aspects. Nevertheless, the results have been contradictory and a direct correlation between transcripts BCR/ABL, the clinic and ethnicity has not been yet found. Although, geographic variation has been already revealed for others leukemia types, thus enhancing the accuracy of prognosis, until now a geographic distribution of CML transcripts remain unrevealed. We report here for the first time, the frequency of different BCR/ABL transcripts in 467 Venezuelan CML patients. The RT-PCR for those transcripts evidenced that 449 (96.1%) of patients had the gene fusion p210BCR/ABL, being 205 (45.6 %) b2a2, 187 (41.7%) b3a2 and 40 (8.8%) b2a2/b3a2 co-expression. The remaining 17 (3.9%) included the expression of variant P190BCR/ABL (e1a2) and its co-expressions: e1a2/b2a2, e1a2/b3a2 and e1a2/b2a2/b3a2. Most of the patients were between 21 and 60 years old and 53% were males. The analysis of automatic sequences showed the T/C polymorphism in some b2a2 transcripts, while b3a2 and co-expressions transcripts did not present it. These results were included in our study on the geographic distribution of the BCR/ABL transcripts. That study revealed that the Asian and Middle East countries (Malaysia, Thailand, Korea, India, China, Japan and Iran) showed the highest frequency of b3a2, while American countries (Brazil, Mexico and Venezuela) presented b2a2 as the highest frequency found. This geographical distribution of transcripts was found to have a pattern according to longitude: increasing the relative expression of b3a2 from west to east. As for the relative expression of b2a2 and b3a2 transcripts by ethnic groups, it showed three main groups: Asians and Middle Easterns express mainly b3a2 transcript, Europeans (Caucasians European) express both transcripts, whereas Mestizos (mulattos, Caucasians and Amerindians) express mainly b2a2 transcript. This geographical distribution pattern suggests that the relation between clinical features and CML transcripts could be masked by underlying factors such as ethnicity and geographic location.