Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q

Abstract

We used spectral karyotyping (SKY) to study 29 adults with acute myeloid leukemia and a complex karyotype containing one to nine abnormalities that were not fully identifiable by G-banding. SKY showed the origin of rings and unidentified material in unbalanced translocations in all cases and the origin of markers in most, allowing reinterpretation of 136 aberrations and discovery of three aberrations hidden in normal chromosomes. SKY confirmed 10 and refined the interpretation of three balanced aberrations recognized by G-banding and identified another nine balanced aberrations, including a novel translocation involving the RUNX1 gene. Eleven of 32 deletions found by G-banding were shown to be cryptic translocations or insertions, including three of four chromosome 3 deletions, two of three del(7q), and two of 12 del(5q). Of the 92 chromosomes deemed lost entirely by G-banding, 63 (68%) were shown to be involved in structural aberrations. This was especially true for -21 (eight of eight patients), -5 (five of six patients), -20 (seven of nine patients), and -18 (six of 12 patients). Unexpectedly, SKY uncovered a hidden overrepresentation of segments from at least one chromosome in 21 patients. The most frequently overrepresented was 21q, found in eight patients, including four with high-level 21q amplification. Fluorescence in situ hybridization showed that the RUNX1 gene was not the target of amplification in seven of these patients. Also frequently gained were 11q (in seven patients, including three with high-level MLL gene amplification) and 22q (in seven patients). We conclude that SKY considerably enhances the accuracy of karyotype interpretation, and that amplification of chromosomal material may play a greater role in leukemogenesis than has been recognized.

Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on 5098 unselected cases reported in the literature 1974–2001

“…Recently, several studies using multicolor fluorescence in situ hybridization have shown that complex karyotypes with monosomies of chromosomes 5 and 7 often harbor marker chromosomes containing material from these chromosomes and that many deletions, including 5q deletions, have been shown to be unbalanced translocations. 57,58 Thus, the present conclusion concerning differences between whole and partial losses of chromosomes 5 and 7 may well be modified when more data based on molecular cytogenetics have been collected. The chromosomal abnormalities shown to be more common in de novo disease were +8 as a sole anomaly, balanced changes as such, t(8;21), t(9;22), t(15;17), inv (16), and 21q22 translocations in general in AML (Table 2) and −Y, 5q−, and 20q− as sole anomalies and +8 in MDS (Table 3).…”

Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML

“…[10][11][12][13][14][15] Patient characteristics, karyotypes, results of FISH, and mutation status of TP53 and AML1 of the three cases are shown in Table 1.…”

“…This phenomenon has been observed in approximately 2% of patients with childhood acute lymphoblastic leukemia (ALL), [6][7][8][9] but to our knowledge only in seven cases of de novo MDS and AML. [10][11][12][13][14][15] In these seven patients the mutational status of TP53 was not examined. In t-MDS and t-AML a similar amplification or duplication of chromosome band 11q23 including the unrearranged MLL gene has been observed in 17% of the patients closely associated with mutations of the TP53 gene.…”

The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia

“…Among the genetic markers that has been previously studied in CN-AML patients are Fms-related tyrosine kinase 3 gene (FLT3) mutations [2][3][4][5], the nucleophosmin gene (NPM1) mutations [6][7][8][9][10][11][12][13][14][15], ERG [16,17] and BAALC [18][19][20][21][22] expression levels. Although studies concerning the prognostic relevance of BAALC [18] and ERG expression [16,17] in adult AML patients with CN AML become fully clear; the studies regarding their expression and prognostic impact in pediatric AML are few and of controversial results.…”