Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype

Abstract

Patients with acute myeloid leukemia (AML) harboring three or more acquired chromosome aberrations in the absence of the prognostically favorable t(8;21)(q22;q22), inv(16)(p13q22)/t(6;16)(p13;q22), and t(15;17)(q22;q21) aberrations form a separate category - AML with a complex karyotype. They constitute 10% to 12% of all AML patents, with the incidence of complex karyotypes increasing with the more advanced age. Recent studies using molecular-cytogenetic techniques (spectral karyotyping [SKY], multiplex fluorescence in situ hybridization [M-FISH]) and array comparative genomic hybridization (a-CGH) considerably improved characterization of previously unidentified, partially identified, or cryptic chromosome aberrations, and allowed precise delineation of genomic imbalances. The emerging nonrandom pattern of abnormalities includes relative paucity, but not absence, of balanced rearrangements (translocations, insertions, or inversions), predominance of aberrations leading to loss of chromosome material (monosomies, deletions, and unbalanced translocations) that involve, in decreasing order, chromosome arms 5q, 17p, 7q, 18q, 16q, 17q, 12p, 20q, 18p, and 3p, and the presence of recurrent, albeit less frequent and often hidden (in marker chromosomes and unbalanced translocations) aberrations leading to overrepresentation of segments from 8q, 11q, 21q, 22q, 1p, 9p, and 13q. Several candidate genes have been identified as targets of genomic losses, for example, TP53, CTNNA1, NF1, ETV6, and TCF4, and amplifications, for example, ERG, ETS2, APP, ETS1, FLI1, MLL, DDX6, GAB2, MYC, TRIB1, and CDX2. Treatment outcomes of complex karyotype patients receiving chemotherapy are very poor. They can be improved to some extent by allogeneic stem cell transplantation in younger patients. It is hoped that better understanding of genomic alterations will result in identification of novel therapeutic targets and improved prognosis in patients with complex karyotypes.

Figure 1

Complex karyotype containing 8 chromosome abnormalities detected in a patient with acute myeloid leukemia, analyzed using spectral karyotyping (SKY). Each chromosome is represented twice, by G-banding-like inverted and contrast-enhanced DAPI-stained image on the left and SKY image shown in classification colors on the right. This karyotype contains several chromosome abnormalities relatively common in AML with a complex karyotype: an unbalanced translocation between chromosomes 3 and 17 leading to loss of material from 3p and chromosome 17 (yellow arrow), an unbalanced translocation between chromosomes 3 and 5 resulting in partial loss of 5q (green arrow), trisomy of chromosome 8 (blue arrow), loss of one copy of chromosome 17 (grey arrow) and a complex rearrangement between chromosome 10 and 21 leading to gain of material from 21q (red arrow). Also present are: a complex rearrangement of chromosome 15 resulting in amplification of 15q material (white arrow), abnormal chromosome 10 (orange arrow) and a small marker chromosome whose origin could not be established reliably by SKY technique (pink arrow).

Figure 2

Metaphase cells from an AML patient with a complex karyotype that contains an abnormal “sandwich-like” derivative chromosome comprised from several interchanging segments from chromosomes 7 and 21, analyzed using SKY (A) and whole-chromosome-painting probes for chromosomes 7 (B) and 21 (C). Inverted and contrast-enhanced DAPI images are shown on the left. SKY in display colors (A) and FISH images (B and C) are shown on the right. Long arrows point to the centromeric area of the abnormal “sandwich-like” derivative chromosome, short arrows denote normal chromosomes 7 (A and B) and 21 (A and C). A: Full metaphase cell analyzed using SKY. B. Partial metaphase hybridized with the whole-chromosome-painting probe for chromosome 7. C. Partial metaphase hybridized with the whole-chromosome-painting probe for chromosome 21.