**1.3 Variants of Ph chromosome**

The Ph is detected by G-band karyotyping in around 90% of CML patients among whom 5–10% may have variant chromosome types [23–25]. Variants of Ph chromosome are characterized by the involvement of another chromosome in addition to chromosomes 9 and 22. Variant rearrangements can be simple or complex. Simple-type variants involve another chromosome, for example, t (9; 22; 6). Complex variants participate in the translocation of two or more chromosomes, besides chromosomes 9 and 22 [26, 27].

Variant Ph breakpoints occur in hotspots across the genome, usually in the G-light bands, within the cytosine and guanine (CG) richest parts of the genome [28]. CG content correlates with chromatin condensation and transcription activity; that is, open chromatin is transcriptionally active and relatively likely to undergo breakage and repair with a consequent tendency to illegitimate recombination and translocation [24].

Variant Ph chromosomes are distinguished from additional chromosomal abnormalities or clonal evolution that drives disease progression. The clonal evolution is a reflection of a genetic instability that characterizes the transition to advanced phase [29]. However, the mechanism of variant Ph generation and the molecular bases of biological differences between classic Ph and variant Ph chromosomes are not fully understood [30].

In atypical CML (aCML), patients are Ph-negative. This leukemia presents initial characteristics and clinical course similar to those of Ph-positive patients. However, Ph-negative patients have more heterogeneous characteristics, often more aggressive disease progresses with worse prognosis [31].
