Fluorescence in situ hybridization and comparative genomic hybridization characterized 6p rearrangements in eight primary and in 10 secondary myeloid disorders (including one patient with Fanconi anemia) and found different molecular lesions in each group. In primary disorders, 6p abnormalities, isolated in six patients, were highly heterogeneous with different breakpoints along the 6p arm. Reciprocal translocations were found in seven. In the 10 patients with secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS), the short arm of chromosome 6 was involved in unbalanced translocations in 7. The other three patients showed full or partial trisomy of the 6p arm, that is, i(6)(p10) (one patient) and dup(6)(p) (two patients). In 5/7 patients with unbalanced translocations, DNA sequences were overrepresented at band 6p21 as either cryptic duplications (three patients) or cryptic low-copy gains (two patients). In the eight patients with cytogenetic or cryptic 6p gains, we identified a common overrepresented region extending for 5–6 megabases from the TNF gene to the ETV-7 gene. 6p abnormalities were isolated karyotype changes in four patients. Consequently, in secondary AML/MDS, we hypothesize that 6p gains are major pathogenetic events arising from acquired and/or congenital genomic instability.
In hematological malignancies, rearrangements at the short arm of chromosome 6 are characterized by heterogeneous chromosome abnormalities, breakpoints and partner chromosomes. In primary disorders, specific clinical–hematological and genetic entities have been identified. In acute myeloid leukemia (AML), the t(6;9)(p23;q34)/DEK-CAN is associated with bone marrow dysplasia and basophilia, a high incidence of FLT3 mutations and unfavorable prognosis;1, 2 in B-cell non-Hodgkin's lymphoma (B-NHL), the H4 or SRP20 gene deregulates the BCL-6 oncogene as a result of t(3;6)(q26;p21);3, 4 in B-NHL and multiple myeloma (MM) with t(6;14)(p21;q32), the IgH promoter aberrantly activates the cyclin D3, which is overexpressed;5, 6 in MM with t(6;14)(p25;q32), the IgH gene juxtaposes to MUM/IRF4.7
In secondary myelodysplastic syndrome (MDS) and AML, 6p rearrangements account for less than 2% of cytogenetic abnormalities.8 Although mainly found in complex karyotypes, which also bear −5/del(5)(q) and/or −7/del(7)(q), rare cases of isolated 6p rearrangements have been observed.9, 10, 11 Deletions, balanced and unbalanced translocations, insertions and duplications have been described with a der(1)t(1;6) change as the only recurrent abnormality.12, 13, 14 No specific correlations have been found with previous exposure because 6p rearrangements have been linked not only to chemo- and/or radiotherapy, but also to different environmental agents.9, 10
We used a molecular cytogenetic approach to characterize 6p rearrangements in primary and secondary myeloid disorders and found different molecular lesions in each clinical subgroup.
Patients, materials and methods
Inclusion criteria were diagnosis of a myeloid disorder, a 6p rearrangement and availability of fixed cells for fluorescence in situ hybridization (FISH) studies. Patients were retrieved from the Departments of Hematology, Universities of Florence, Bologna, Perugia, the ‘S Bortolo’ Hospital in Vicenza, and the ‘San Camillo’ Hospital in Rome, Italy; the Servei of Hematologia, Hospital Sant Pau, Barcelona, Spain; the Health Physics and Environmental Hygiene Lab, NCSR Demokritos, Athens, Greece; the Laboratoire de Biopathologie, Institut Paoli-Calmettes, INSERM U119, Marseille, France.
Bone marrow cells were cultured for 24–48 h. Metaphases were G-banded with Wright stain, and karyotypes were described according to the International System for Human Cytogenetic Nomenclature.15
Fluorescence in situ hybridization
Metaphase FISH was performed as described16 with a panel of 6p DNA clones ordered from band p25 to band p12 as shown in Table 1. To fully characterize 6p unbalanced translocations, whole chromosome painting (WCP) for chromosomes 1, 6, 8, 16, 18, 19 and for the short arm of 20, probes for the alpha satellite region of chromosomes 1/5/19 (D1Z7/D5Z2/D19Z3) and chromosome 6 (D6Z1) were used (Oncor, Appligene Gaithersburg, MD, USA; Vysis, Stuttgart, Germany; ListarFish, Milan, Italy). Multi-color FISH (M-FISH) experiments with the 24XCyte human multi-color FISH probe kit (MetaSystem, Zeiss, Altlussheim, Germany) were performed in patient 8 (Table 2). Five to ten abnormal metaphases were evaluated by FISH and G-banding in each experiment.
Eleven patients were investigated by interphase-FISH with RP11-888J3 for FHIT/3p14, cos148B6 and cos179A6 for ETV6/12p13, RP11-199F11 for TP53/17p13, RP5-1106L7 for AML1/21q22 and with the LSI CSF1R SO/D5S721:D5S23 SG/5q33, LSI D7S486 SO/CEP 7 SG/7q31 and LSI D13S25 SO 13q14/D13S25 (LSI probes by Vysis, Downers Grove, IL, USA). Analysis of 200 nuclei was carried out for each probe. Bone marrow samples from healthy donors were added in each experiment as controls. The cutoffs for monosomy/deletion (3p14/FHIT 5%, 5q33/CSF1R 2%, 7q31/D7S486 1.96%, 12p13/ETV6 6%, 13q14/D13S25 4.3%, 17p13/TP53 4.7%, 21q22/AML1 4.7%) and for trisomy/splitting (3p14/FHIT 1.5%, 5q33/CSF1R 0.5%, 7q31/D7S486 0.5%, 12p13/ETV6 2.5%, 13q14/D13S25 1%, 17p13/TP53 2%, 21q22/AML1 2.5%) were set at the upper limits for false positive results as established by our laboratory standard.16, 17
Comparative genomic hybridization
Comparative genomic hybridization (CGH) was performed as already reported.18 Chromosomal regions were considered overrepresented if the corresponding green/red ratio exceeded 1.17 and underrepresented if the ratio was below 0.83. Negative control thresholds were established on profiles from hybridization of two differently labeled DNA samples from healthy donors. FISH and CGH analyses were carried out using a fluorescence microscope (Provis, Olympus, Milan, Italy) equipped with a cooled CCD camera (Sensys, Photometrics) run by PathVysion softwares (Vysis, Stuttgart, Germany).
In secondary AML/MDS, 6p rearrangements were isolated in four cases and included in complex karyotypes in six. The 6p changes included i(6)(p10) (patient 1), 6p duplication (patients 2 and 3) and unbalanced translocations (patients 4–10) with diverse chromosome partners or unidentified material (Table 2). In primary AML/MDS 6p abnormalities were isolated in six cases, associated with one numerical change in 1 and included in complex karyotype in 1. Balanced translocations with diverse chromosome partners were present in patients 11–17. Patient 18 had add(6)(p) (Table 3).
Metaphase fluorescence in situ hybridization and multi-color FISH
Secondary acute myeloid leukemia/myelodysplastic syndrome
In patient 1, all 6p probes were present in three copies as expected: one on normal 6 and two on each arm of i(6)(p10) (Figure 1a). In patients 2 and 3 with dup(6)(p), both duplications fell within band p21 and extended, respectively, to include clones RP1-153G14 to RP3-381E2 and cosmid CAH5 to RP4-753D5 (Figure 1b). Breakpoints of 6/7 unbalanced translocations (patients 4–8 and 10) clustered at band p21; the other breakpoint in patient 9 was at band p23 (Table 1).
In patients 4, 6 and 7, with unbalanced translocations, FISH showed cryptic duplications of a genomic region contiguous to the translocation breakpoints, at band p21 (Figure 1c and d). In patients 5 and 8, a low-copy gain with five copies of DNA clones mapping at band p21, was present on der(6) and/or inserted in other derivative chromosomes (Figure 1e and f). In all cases, the 6p21 gain was narrowed to a 5–6 megabase DNA segment extending from the tumor necrosis factor (TNF) gene (cosmid CAH5 at the telomeric side) to ETV-7 (RP1-50J22 at the centromeric side) (Tables 1 and 4). Patients 9 and 10 showed no 6p21 gain.
In patients 5–8 and 10, WCP, centromeric probes and multi-FISH fully characterized complex karyotypes and classified 6p changes (Table 2).
Primary acute myeloid leukemia/myelodysplastic syndrome
6p breakpoints were mapped at bands p24–p23 in four cases and at band p21 in the other four (Table 1).
Interphase fluorescence in situ hybridization
This study was performed in patients 2–4 and 6–9 (Table 2) with secondary and in patients 12–14 and 17 (Table 3) with primary AML/MDS. In patient 7, probes for 12p13/ETV6 were monosomic in 92% of nuclei, concurring with the presence of an unbalanced 12p translocation. Monoallelic loss of probes for 5q33/CSF1R and 7q31/D7S486, in patient 6, and for 3p14/FHIT, 5q33/CSF1R, and 7q31/D7S486, in patient 8, with one signal in 40–90% of nuclei, was in accord with the karyotype showing partial or full loss of the corresponding chromosomes (Table 2). In patient 14, probes for 12p13/ETV6 gave split signals in 50% of nuclei indicating its involvement in t(6;12)(p21;p13), which was further demonstrated by metaphase FISH (data not shown). No cryptic genomic rearrangements were found in the other patients.
Comparative genomic hybridization
Comparative genomic hybridization was performed in patients 1 and 8. In patient 1, CGH detected gains of chromosome 1 at bands 1p31–p32 and 1p36, a gain of the entire short arm of chromosome 6 and losses of the 5q11–q23 region, the 12q21 band, the long arm of chromosome 16 and the 22q13 band. In patient 8, we observed gains of the short arm of chromosome 5 and band 6p21, and losses of chromosome 3 in the 3p11–p21 and 3q11–q23 regions, 5q13.3–qter, 6p24–pter and 7q31–qter.
Cytogenetic and molecular findings indicate two distinct genotypes underlying 6p rearrangements in primary and secondary AML/MDS. Primary AML/MDS showed a low incidence of complex karyotypes and a high incidence of reciprocal translocations, confirming other observations.19 In secondary AML/MDS, complex karyotypes in 60% of patients included at least one numerical or structural aberration that is typically associated with therapy-related AML/MDS (−5/5q− in four patients, −7/7q− in three, monosomy 18 in three) (Table 2). The short arm of chromosome 6 was involved in unbalanced translocations in 7/10 patients. In the other three, the 6p arm gains included full or partial trisomy, that is, i(6)(p10) (patient 1) and dup(6)(p) (patients 2 and 3). In patients 4–9 with unbalanced translocations, DNA sequences were overrepresented at band 6p21 as either cryptic duplications or cryptic low-copy gains (Figure 1). Gains varied in size; the smallest common overrepresented region extended for 5–6 megabases.
As duplications/low-copy gains occurred in secondary AML and in the Fanconi anemia (FA) patient, external toxic insults and congenital instability appear to share the same genetic pathway. In fact no association emerged with specific toxic agents, as both environmental/professional exposure and chemo-/radiotherapy were documented in all our patients: three had undergone chemotherapy, one chemo- and radiotherapy, two were farmers exposed to pesticides and insecticides, two were spray painters, one was a plumber exposed to solvents and glues. The patient with FA had congenital chromosomal instability.20
Here, we demonstrate for the first time that a gain of a 5–6 megabases genomic segment at 6p21 is recurrent and underlies heterogeneous chromosomal changes. Cytogenetically, amplifications are frequently associated with double minutes or homogenously staining regions.21, 22 which were never observed in our series. We found cryptic 6p gains at the translocation breakpoints of der(6) in cases with duplications and/or within derivative chromosome partners in cases with low-copy gains. As genomic duplications occur at breakpoints of abnormal chromosomes in several genetic disorders,23, 24 the 6p duplication–recombinations in secondary AML/MDS might mirror congenital events.
Duplicons, which localize in multiple regions of the human genome, appear to mediate homologous recombinations which may change chromosome structure.25 In acquired translocations, one example is the 76 kb identical duplicon at both 9q34 and 22q11 breakpoints in t(9;22)(q34;q11).26
Olfactory receptor (OR) gene clusters are duplicons dispersed throughout the genome, which mediate chromosomal rearrangements in congenital syndromes.27, 28 In our patients five OR clusters are located close to or within the 6p21 common overrepresented region. Their genomic instability could account for the intra-chromosomal (duplications and amplifications) and inter-chromosomal recombinations (translocations). Whether toxic insults or congenital defects of DNA repair worsen the genomic instability at 6p21 needs to be investigated.
Whatever the mechanism, 6p gains impact on the onset and development of many tumors such as NHL, osteosarcoma, lung, breast and ovarian carcinoma, retinoblastoma and uveal melanoma.29, 30, 31, 32, 33, 34, 35 In the U937-I cell line, with its unbalanced 6p translocation at karyotype,18 we detected a cryptic 6p21 duplication/amplification spanning the DNA segment from the BAK/6p21 gene to RUNX2/6p21, which is partially overlapping with the common overrepresented region in the present series of secondary AML/MDS. Interestingly, array CGH found a 6p21–22 gain in two relapsed AML with unbalanced 6p translocations.36
Putative candidate genes in the leukemogenic pathway of secondary AML/MDS with 6p21 gains include the MHC complex, NOTCH-4, BAK, FANCE, ETV-7, HMGIY and FKBP51. It is worth noting that the HMGIY protein is overexpressed in uterine leiomyomata with complex rearrangements involving the 6p arm,37 whereas FKBP51 is overexpressed in megakaryocytes derived from CD34+ cells of patients with idiopathic myelofibrosis.38
In our patients, 6p gains sometimes occur as isolated karyotypic changes. They are never associated with cryptic genomic rearrangements of putative suppressor/oncogenes, which are known to be involved in therapy-related AML/MDS or with TP53 deletions such as are observed in secondary AML/MDS with MLL and AML1 duplications/amplifications.39, 40 Consequently, we hypothesize that 6p gains are major pathogenetic events arising from acquired and/or congenital genomic instability.
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PAC and BAC clones were obtained from the Roswell Park Cancer Institute libraries RPCI-1, RPCI-3, RPCI-5 and RPCI-11, http://www.chori.org/BACPAC. RP5-1106L7 was kindly provided by Dr M Rocchi, University of Bari, Italy; cosmid Cah5 by Dr E Weiss, Ludwig Maximilians Universität, München, Germany; and clones RP1-22O11, RP1-99J17, RP1-162J16, RP1-124L9 and RP3-329A5 by Dr I Ragoussis King's College, London, UK. We thank Dr Geraldine Anne Boyd for assistance in preparing the manuscript. This work was supported by AIRC (Associazione Italiana Ricerca sul Cancro), CNR (Consiglio Nazionale delle Ricerche), MIUR (Ministero per l’Istruzione, l’Università e la Ricerca Scientifica), Fondazione Cassa di Risparmio, Perugia, Associazione ‘Sergio Luciani’, Fabriano, AULL (Associazione Umbra contro le Leucemie e Linfomi) Italy; and Belgian Programme of Interuniversity Poles of Attraction initiated by Belgian State, Prime Minister's Office, Science Policy Programming. BC is supported by a grant from FIRC (Fondazione Italiana per la Ricerca sul Cancro).
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