BCR/ABL1 Extra Fusions in Patients with Chronic Myeloid Leukaemia (CML)

Abstract

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome (Ph), which is originated by a balanced translocation between chromosomes 9 and 22, that is, t(9;22)(q34;q11) results in production of a BCR-ABL1 fusion protein with constitutive Abl kinase activity. In experimental models, the expression of said activity causes expansion of pluripotent stem cells, preferentially favours myeloid lineage differentiation, and inhibits erythroid differentiation [1,2]. The BCR/ABL1 fusion in 22q11 is observed in ~95% of patients with chronic myeloid leukemia (CML). The BCR/ABL1 fusion signal on the derivative chromosome 22 is present in most CML patients. In 5-10% of cases, this signal is generated by variant rearrangements (variant Ph) that involve other genomic regions [3-7]. More than 600 CML cases with variant rearrangements have been reported. The breakpoint distribution clearly exhibits a non-random pattern, with marked clustering to some chromosome bands, such as 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13, which suggests that these regions may be particularly prone to breakage. In addition, some specific variants are also known to be more frecuent, with the two translocations t(3;9;22)(p21;q34;q11) and t(17;22)(q25;q11) both having been reported in more than 10 cases [8]. The occurrence of additional chromosomal aberrations (ACA) in Ph-positive CML is strongly associated with disease progression and has been interpreted as a sign of clonal evolution as well as chromosomal instability. Mitelman et al. [9] identified +Ph, +8, and i(17q) as the most common secondary changes that occur in nearly 90% of the cases with additional abnormalities. These three abnormalities were proposed to follow the ‘major route’ of clonal evolution, whereas other changes, which evolved more rarely, were suggested to follow the ‘minor route’ [9]; the terms ‘major’ and ‘minor’ refer to frequencies of the aberrations but not to the pathogenetic impact. Thus the three major route changes, followed by +19, were the most common ACA. Other additional chromosomal abnormalities take place in less than 10% of the cases, the most frequent being –Y, +21, +17, –7, and –17. On the other hand, no apparent differences in ACA between CML with standard Ph and CML cases with Ph variants are observed. The most common additional chromosomal changes are +8 (34%), +Ph (30%), i(17q) (20%), +19 (13%), –Y (8% of