Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2–10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60–80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), –Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11–14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12–21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, althoug...

BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress

“…+12 [7], +12 Â 2 [3] der(X)t(X;8) [6], der(X)t(X;8)x2 [3] 1.2 ± 0.6* 2.5 ± 1.1** B/A-VE (13) +12 [7] 0 0 0.5 ± 0.5 VE in vivo B/A-C (13) +12 [13] der(X)t(X;8) [6], der(14)t(8;14) [6], der(X)t(X;14), [6], der(X)t(X;9) [1]…”

Fusion tyrosine kinases: a result and cause of genomic instability

“…Genetic aberrations leading to malignant progression of the disease CML cells accumulate genetic abnormalities during the course of the disease (Rowley and Testa, 1982;Alimena et al, 1987;Johansson et al, 2002;Shet et al, 2002;Calabretta and Perrotti, 2004). The aberrations associated with the progression of BCR/ABL-positive CML chronic phase to the aggressive blast crisis (CML-BC) include additional chromosomes (Ph 1 , þ 8, þ 19), isochromosome 17q (associated with the loss of p53), reciprocal translocations (3;21 and 7;11 -associated with the expression of AML-1/Evi-1 and NUP98/ HOXA9 fusion proteins, respectively), other translocations and inversions associated with AML/myelodysplasia (inv(3), t(15;17)), loss-of-heterozygosity at 14q32, homozygous mutations/deletions of pRb and p16/ARF, and mutations in p53 and RAS (reviewed by Calabretta and Perrotti, 2004).…”

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

“…In fact, along with other frequent genetic and molecular abnormalities (e.g. double Ph 1 chromosome, p53 inactivation) (Johansson et al, 2002), increased expression and activity of the BCR/ABL oncoprotein is frequently observed during CML disease progression and in blast crisis CML (Elmaagacli et al, 2000;Jamieson et al, 2004;Barnes et al, 2005b), and sustained BCR/ABL expression in myeloid progenitor cell lines induces phenotypic changes (i.e. differentiation arrest) characteristic of CML-BC .…”