A novel insertion ins(18;5)(q21.1;q31.2q35.1) in acute myeloid leukemia associated with microdeletions at 5q31.2, 5q35.1q35.2 and 18q12.3q21.1 detected by oligobased array comparative genomic hybridization
© Kjeldsen; licensee BioMed Central Ltd. 2014
Received: 18 July 2014
Accepted: 28 August 2014
Published: 25 September 2014
Nonrandom clonal chromosomal aberrations can be detected in approximately 55% of adult patients with acute myeloid leukemia (AML). Recurrent cytogenetic abnormalities play an important role in diagnosis, classification and prognosis of AML. However, several chromosomal abnormalities have not been completely determined or characterized, primarily because of their low incidence and limited amount of data.
We characterized an AML patient with a novel apparently balanced insertion ins(18;5)(q21;q31.2q35.1) that was cryptic by G-banding. The rearrangement was further examined by molecular cytogenetic methods and oligobased high-resolution array CGH (oaCGH) analysis. We show that an approximately 31.8 Mb large segment from chromosome 5 bands q31.2 to q35.1 has been inserted, by a direct mechanism, into chromosome 18 between bands q12.3 and q21.1. The insertion was unbalanced with concurrent submicroscopic deletions at 5q31.2 (approximately 0.37 Mb in size), 5q35.1q35.2 (approximately 1.98 Mb in size), and 18q12.3q21.1 (approximately 2.07 Mb in size). The microdeletions affect genes on 5q and 18q that have been associated with hematological malignancy and other cancers. A novel juxtaposition of the genes NPM1 and HAUS1 at 5q35.1 and 18q21.1, respectively, was detected by FISH analysis. Searching the literature and the Mitelman database revealed no previously reported ins(18;5) cases. Interestingly, however, two AML patients with translocation t(5;18)(q35;q21) encompassing the 5q35 and 18q21 breakpoint regions as detected in our present ins(18;5) patient have been reported.
It is well-known that cytogenetic abnormalities on the long arm of chromosome 5 affect hematopoiesis. However, the precise mechanism of their involvement in myeloid transformation is elusive. Our present data shed new light onto the frequent abnormalities on 5q as well as to the less frequent abnormalities observed on 18q in myeloid malignancies. In addition, we show that oaCGH analysis is a useful adjunct to revealing submicroscopic aberrations in regions of clinical importance. Reporting rare and nonrandom chromosomal abnormalities contribute to the identification of the whole spectrum of cytogenetic abnormalities in AML and their prognostic significance.
KeywordsAcute myeloid leukemia ins(18;5) oaCGH analysis Chromosomal insertion Microdeletion Cryptic chromosomal aberration del(5q) add(18q)
In acute myeloid leukemia (AML) recurrent nonrandom chromosomal aberrations occur in approximately 55% of the patients. Until now about one hundred different chromosomal rearrangements have been uncovered in AML. The rearrangements mostly include balanced translocations, inversions, deletions, amplifications, monosomies and trisomies . It is well established that cytogenetic analysis is an important prognostic factor that influences therapeutic decision-making and disease outcome because the various chromosomal rearrangements play critical roles in the molecular pathogenesis -.
Myeloid malignancies are subdivided into distinct disease entities on the basis of specific cytogenetic or molecular genetic abnormalities . Cytogenetic characterization defines three different risk groups: favorable, intermediate, and adverse . Molecular characterization has revealed that mutations in FLT3 and NPM1 define molecular subgroups with prognostic relevance . AML patients that do not fulfill WHO criteria for other categories are grouped together in the "AML, not otherwise specified (NOS)" category, which do not provide prognostic information. AML is a heterogeneous disease with respect to clinical and biological features. Hence, it is very important to better define less frequent chromosomal rearrangements in AML patients to identify the full spectrum of molecular prognostic factors.
Here we report the characterization of a novel cryptic insertion ins(18;5)(q21.1;q31.2q35.1) in a patient with de novo AML, who, as detected by oligobased high-resolution array CGH (oaCGH) analysis, also harbored three concurrent submicroscopic microdeletions 5q31.2, 5q35.1q35.2, and 18q12.3q21.1 in his leukemic cells. Two previous AML patients with the translocation t(5;18)(q35;q21), and similar breakpoints as observed in our patient, have been reported. We review these patients and discuss the possibility that the ins(18;5) detected in our present patient is a variant of this rare non-random chromosomal abnormality t(5;18).
A 37-year-old male Caucasian, previously well, presented with 4-5 weeks of fatigue, increasing paleness and dyspnea. In this period and on admission there were no febrilia, infections, or signs of bleeding except for one occasion of melaena 3 weeks prior to admission. He had an unintended weight loss of five kg from 91 kg. Bone marrow (BM) examination showed marked hypercellularity with medium-sized mononuclear blasts and an 80% proportion of highly proliferative blasts, staining CD4+, CD7+, CD13+, CD43+, CD117+, CD123+, CD34-, HLA-DR+, CD56-, and TdT-. Hematological examination included a total white blood cell count of 4.49 × 109/L, hemoglobin of 5.1 mmol/L and, platelets of 24 × 109/L. Segmented neutrophil count was 0.70 × 109/L. The patient's father's cousin and great grandmother in his mother's line had leukemia. The patient had no comorbidity and had no previous history of being treated with chemotherapy or exposed to radiation. He had been smoking until 3 years prior to his AML diagnosis with an estimated pack years of 15. There was no information on possible occupational hazards.
Our patient entered the AML-17 treatment protocol (Trial reference ISRCTN55675535). This protocol is a randomized multi-arm Phase III study designed by the AML Working Group of the National Cancer Research Institute (NCRI) and the Hematology Oncology Study Group in Acute Myeloid Leukemia and high risk Myelodysplastic Syndrome (MDS) in adults (http://aml17.cardiff.ac.uk/). In this interventional treatment protocol, AML and high risk MDS patients are randomized to one of five subgroups for induction therapy, then risk assessed, and randomized to FLT3 inhibitor if mutated or high risk chemotherapy with or without mTOR inhibition. According to the protocol our patient was initially treated with DA because of intermediate-risk cytogenetics. Molecular genetic analysis of his bone marrow cells at diagnosis showed an internal tandem duplication mutation in FLT3 (FLT3-ITD) and NPM1 wt, and was then assigned to high-risk leukemia. He received FLAG-IDA treatment according to AML-17 and obtained complete remission 28 days after admission as evaluated by pathology, flowcytometry, cytogenetics and molecular genetics.
Cytogenetic and multicolor FISH analyses
The maximum regions of microdeletions involved in the other break point regions are: 1) at chromosome band 5q31.2 the microdeletion encompasses the oligonucleotide probes A_16_P37384388 to A_16_P17320593 mapping from 138,390,821 to 138,769,054; 2) at chromosome bands 5q35.1-q35.2 the microdeletion encompasses the oligonucleotide probes A_16_P37464643 to A_16_P17402538 mapping from 170,768,753 to 172,758,763; and 3) at chromosome bands 18q12.3-q21.1 the microdeletion encompasses the oligonucleotide probes A_16_P41020231 to A_16_P03359511 mapping from 39,887,338 to 41,970,952. The minimum region of microdeletions in the involved break point regions are: 1) at chromosome band 5q31.2 the microdeletion encompasses the oligonucleotide probes A_16_P17319737 to A_16_P17320525 mapping from 138,403,448 to 138,746,932; 2) at chromosome bands 5q35.1-q35.2 the microdeletion encompasses the oligonucleotide probes A_18_P15493901 to A_16_P01397609 mapping from 170,771,533 to 172,741,295; and 3) at chromosome bands 18q12.2-q21.1 the microdeletion encompasses the oligonucleotide probes A_16_P20842291 to A_16_P20847704 mapping from 39,899,537 to 41,952,135. From these results the respective estimated minimum to maximum deletion sizes are: 1) at 5q31.2: 343.5-378.2 kb; 2) at 5q35.1-q35.2: 1,969.8-1,990.0 kb; and 3) 18q12.3-q21.1: 2,052.6-2,083.6 kb. The genes located in the minimal deleted regions are summarized in Figure 3.
Taken together we have shown that an approximately 31.8 Mb large chromosomal segment encompassing the bands 5q31.2q35.2 was cut out and inserted by a direct mechanism between chromosome bands q12.3 and q21 on chromosome 18 (Figure 4B and C). The insertion was unbalanced with concurrent submicroscopic deletions at 5q31.2 (approximately 0.37 Mb in size), 5q35.1q35.2 (approximately 1.98 Mb in size), and 18q12.3q21.1 (approximately 2.07 Mb in size). As a result of this complex rearrangement the following band regions became juxtaposed: 5q31.2-5q35.2, 18q12.3-5q31.2, and 5q35.1-18q21.1. By in silico analysis of the involved regions it was found that the 5'-part of SIL1 (spanning exons 1-9) at 5q31.2 and the 5'-part of HAUS1 (spanning exons 1-4) were deleted. A fusion of the chromosomal regions 5q35.1 and 18q21.1 spanning the NPM1 and HAUS1 genes, respectively, was confirmed by FISH analysis with the RP11-117L6 and RP11-474O19 probes (Figure 4D).
The insertion ins(18;5)(q21.1;q31.2q35.1) detected in the leukemic cells of the presented de novo AML patient is to the best of our knowledge a novel chromosomal abnormality. A systematic review of the literature and a search in the Mitelman database  did not reveal any previous reports on ins(18;5) patients with hematological or other cancers.
Insertions are very rare chromosomal abnormalities, not only in hematological malignancies but also in constitutional genetics where the incidence was estimated to be as low as 1:80,000 . Despite their rarity, several instances of insertion variants of the traditional common translocations have been reported in myeloid malignancy, including ins(8;21)/ins(21;8) and t(8;21)(q22;q22)/RUNX1-RUNXT1, ins(3;5) and t(3;5)(q25;q35)/NPM1-MLF1, and ins(22;9) and t(9;22)(p24;q11.2)/BCR-JAK2. Although the molecular mechanisms for generating the insertions variants are different compared to those of generating the traditional common translocations the insertion variants have similar aberrant fusion genes. Further, the AML patients with the insertion variants exhibit similar morphology and prognosis compared to their traditional translocation counterparts.
Summary of published AML patients with t(5;18)(q35;q21) and present patient with ins(18;5)(q21;q31q35)
WBC (×10 9 /L)
Platelets (×10 9 /L)
BM Morphology: Blast (%), cell size, cellularity
80%, large size, hypocellular
60%, large size
80%, medium size, hypercellular
CD4+, CD13+, CD33+, HLA-DR+, CD38+, CD11c+, CD117+
CD13+, CD33+, HLA-DR+, CD117+, MPO-
CD4+, CD7+, CD13+, CD33+, CD117+, MPO+, CD56-, CD34-, TdT-
AML-M2 (de novo)
AML-M2 (de novo)
AML-M1 (de novo)
0.16 Mb amplification @12q21.1
0.37 Mb deletion @5q31.2
1.98 Mb deletion @5q35.1q35.2
2.07 Mb deletion @18q12.3q21.1
FLT3 ITD, NMP1 wt
BMT in CR1
Obtained CR1, karyotype 46,XY,
Relapse with t(5;18)(q35;q21) and a secondary t(3;12)(p23;p13)
BMT planned in CR1
Died 18 months after initial diagnosis
Together these observations suggest that t(5;18), and perhaps our possible variant ins(18;5), may be associated with a high risk AML FLT3-ITD subgroup although the contribution of each genotypic component is unknown. It is well known, however, that AML patients with a normal karyotype and a high burden of FLT3-ITD often present with a more aggressive disease; and more often relapse after remission -. The impact of FLT3-ITD among other cytogenetic subgroups is not clear ,.
With the aid of oaCGH analysis we detected concurrent submicroscopic deletions at each of the cytogenetic breakpoints involved in the complex rearrangement, including 5q31.2, 5q35.1q35.2 and 18q12.3q21.1. Submicroscopic deletions surrounding the most common recurrent translocations breakpoints have been reported in various leukemia with incidences ranging from approximately 2% to 20%, including t(8;21)(q22;q22), t(9;22)(q34;q11), and t(15;17)(q22;q22) -. The clinical significance of these accompanying submicroscopic deletions is largely unknown because they in some cases were associated with poor therapy response and unfavorable outcome while they in others had no effect. It was hypothesized that deletion of critical genes could account for the possible difference in disease course, or alternatively, that such deletions reflect an underlying genomic instability that may predispose the malignant cells to acquire other genetic abnormalities that confer a worse prognosis.
Simple reciprocal translocations between two non-homologous chromosomes fundamentally require only two chromosomal double stranded DNA breaks (DSBs) followed by an exchange of the resulting fragments before sealing of the breaks. A simple insertion requires three chromosomal DSBs, transfer of the segment and then sealing of the three breaks. When a simple insertion rearrangement is complicated by accompanying submicroscopic deletions in the kilobase-to-megabase size at each of the breakpoints, as described in our patient (Figure 4B and 4C), at least six DSBs are required for the complex rearrangement to occur. The additional submicroscopic deletions could either be a by-product of the chromosomal repair mechanism or part of an initiating event. The major DSB repair pathways in mammalian cells are the homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways, and depending upon the chosen repair pathway aberrant chromosomal rearrangements can be generated . In our patient it is likely that the error-prone NHEJ pathway repaired the respective breakpoints.
Translocations involving chromosome 5q35 are rare clonal abnormalities in hematological cancers . The most common recurrent 5q35 translocations with formation of aberrant fusion genes are: t(2;5)(p23;q35)/NPM1-ALK in anaplastic large cell lymphoma , t(3;5)(q25;q35)/NPM1-MLF1 in AML , t(5;17)(q35;q21)/NPM1-RARA in APL , in t(5;11)(q35;p15)/NSD1-NUP98 in childhood AML , and t(5;11)(q35;q12)/NSD1-FEN1 in AML-M5 . The NPM1 and NSD1 at 5q35 are common translocation partners. The NSD1 gene encodes a nuclear protein involved in transcriptional regulation. No prognostic mutations have been ascribed to this gene in relation to leukemia. The NPM1 gene encodes a nuclear matrix phosphoprotein involved in nucleolar ribosome assembly and protein localization. In addition to being a translocation partner NPM1 can be affected by mutations at the DNA sequence level. A 4 bp insertion in exon 12 in NPM1 is one of the most frequent genetic changes known in AML patients with a normal karyotype AML; and its presence in those patients confers a better prognosis . In our patient we detected no genetic abnormalities in NPM1 except for its juxtaposition to HAUS1 at 18q21.1. In the previously reported AML patients with t(5;18)(q35;q21) there is no information about possible aberrant fusion genes or concurrent additional abnormalities involving the NPM1 or NSD1 at 5q35.
Chromosomal abnormalities of the long arm of chromosome 18 are most often associated with lymphoid malignancies. However, the number of reports of genes on chromosome 18 involved in myeloid malignancy is increasing. The SETBP1 and its intronic MIR4319 at 18q12.3 were recently described to be new players in myeloid malignancy ,. SETBP1 was shown to be overexpressed in secondary AML patients bearing the t(12;18)(p13;q12) while the intronic MIR4319 was downregulated . Although the function of SETBP1 is unknown it has been implicated as a transcriptional regulator of many genes. Recurrent somatic mutations promote leukemic cell proliferation  and appear to be a poor prognostic marker especially in elderly AML patients . In our AML patient we found that eleven RefSeq at 18q12.3q21.1 were completely or partially deleted (Figure 3), and that the SETBP1 and MIR4319 genes were two of the deleted genes. In addition, we found that the 5'-part of HAUS1 at 18q21.1 was partially deleted and that it has become juxtaposed to NPM1 as a result of the complex insertion-deletion rearrangement. However, with the methods we used we cannot establish whether the NPM1 and HAUS1 genes formed an aberrant fusion gene. HAUS1 encodes one of eight subunits of the 390 kDa human augmin complex that is a microtubule-binding complex vital for mitotic spindle assembly . There are no previous reports on chromosomal rearrangements involving this gene.
Monosomy 5 and interstitial deletions of 5q are common chromosomal abnormalities in myeloid malignancy. These aberrations occur in 5-10% of karyotypic abnormal adult AML and are usually associated with complex karyotypes, rapid disease progression and poor outcome ,. In our patient we detected two interstitial microdeletions at 5q, one at 5q31.2 (between 343,5-378,2 kb in size) and another at 5q35.1-q35.2 (between 1.969,8-1.990,0 kb in size). The minor 5q31.2 deletion overlaps with the centromeric commonly deleted region (CDR) of two previously identified CDRs in myeloid malignancies -. Of the CDRs the centromeric CDR at 5q31.1-q32.2 is common in high risk MDS and in AML, while the telomeric CDR at 5q33.1 is associated with 5q-syndrom. The identification of pathogenic genes on 5q has proven to be challenging because most patients have extensive deletions encompassing both CDRs . In a large SNP-based study it was found that among 1,115 examined patients with myeloid malignancies 12% had 5q deletions with a median size of 71,4 Mb ranging from 1.9 Mb to 131.28 Mb (whole arm) .
Since no single gene on 5q has been proven to be responsible for high risk myeloid malignancies a haploinsufficiency model has been proposed, reviewed in . According to this model, loss of a single allele of more than one gene on 5q may act in concert to alter hematopoiesis, promote self-renewal of hematopoietic stem and progenitor cells (HSPCs), induce apoptosis of hematopoietic cells, and disrupt differentiation ,. A number of candidate tumor-suppressor genes located at the centromeric CDR at 5q31 (including CDC25C, EGR1, HSPA9, CTNNA1, and DIAPH1) have been implicated in the development of high risk MDS/AML. In our patient we found that six and seventeen RefSeq genes at 5q31.2 and 5q35.1q35.2, respectively, were completely or partially deleted as illustrated in Figures 3 and 4D. It is noticed that the alpha-1 E-catenin gene, CTNNA1, at 5q31.2 is not involved in copy number alterations while the 5'-part of the downstream neighbor gene SIL1 is deleted. The CTNNA1 gene is a tumor suppressor gene that has been associated with progression and poor prognosis in leukemia . The SIL1 gene has not previously been reported to be directly involved in myeloid malignancy although it often is one of the many genes that are deleted in high risk AML/MDS patients with del(5q). It encodes a nucleotide exchange factor that is important for the function of glucose-regulated protein 78 (GRP78). GRP78 is known as a stress-inducible endoplasmic reticulum (ER) chaperone protein and serves as a master initiator of ER stress signaling . Accumulation of unfolded proteins results in GRP78 activation via SIL1 and subsequently activation of the unfolded protein response (UPR). Proteasome inhibitors, such as bortezomib, suppress the degradation of unfolded proteins and trigger ER stress leading to activation of UPR and subsequently apoptotic signals. Although bortezomib is mainly used for treatment of multiple myeloma  and mantle cell lymphoma  it has in some instances been shown to be an effective agent for treatment of 5q- MDS . The combination of genes that are completely or partially deleted in myeloid malignancies with interstitial deletions of 5q might contribute to the heterogeneity of high risk AML/MDS patients.
Application of array-based CGH analysis has not only significantly improved the detection rate of chromosome aberrations in patients with hematological malignancy compared to traditional cytogenetics - but also uncovered concurrent microdeletions in patients with apparently balanced translocations ,. The present study, add to the knowledge of chromosomal aberrations and indicate that oaCGH is a useful adjunct to revealing submicroscopic aberrations in genomic regions of clinical importance.
The present study characterizes a high-risk de novo AML patient and reports on a novel rather complex insertion ins(18:15)(q21;q31.2q35.1) with concurrent submicroscopic deletions at 5q31.2, 5q35.1q35.2 and 18q12.3q21.1. The rearrangement might be a variant of the chromosomal translocation t(5;18)(q35;q21), which previously was reported in two cases with high-risk de novo AML. This study also highlights the clinical usefulness of oaCGH analysis to identify additional submicroscopic copy number aberrations. We have narrowed the 5q31.2 CDR in AML and provided new insight to the putative role of the 5q31.2 deletion in myeloid malignancy. In addition, we have uncovered a novel fusion of the chromosomal regions at 5q35 and 18q21.1 containing the genes NPM1 and HAUS1, respectively, as a result of the complex insertion-deletion rearrangement. This study contributes to the identification of the whole spectrum of cytogenetic abnormalities in AML and their prognostic significance.
Chromosome analysis was done on G-banded chromosomes prepared after short-term unstimulated culturing of cells obtained from bone marrow at diagnosis, and G-banding performed on PHA-stimulated peripheral blood cells as described . Karyotypes were described according to ISCN .
Fluorescent in situ Hybridization (FISH) analysis
Human multicolor FISH were done according to manufacturer's instructions using the following XCyting multicolor FISH probes: 1) 24-color karyotyping was done with the 24XCyte consisting of 24 different chromosome painting probes, 2) mBanding with XCyte 5 and XCyte 18 probes consisting of a series of partial chromosome paints for sequential partially overlapping chromosome regions of a single chromosome (MetaSystems, Altlussheim, Germany). Each of the XCyte probes was labeled with one of five fluorochromes or a unique combination thereof (combinatorial labeling). Metaphases were counterstained with 4',6-diamidino-2-phenylindole (DAPI). Image capture was done with an automated Zeiss Axio Imager.Z2 equipped with a CCD-camera (CoolCube1) and appropriate filters using Isis software (MetaSystems). Karyotyping was done using the 24-color mFISH upgrade package, ISIS, including mBanding.
Summary of custom made BAC-based probes for characterization and validation of oaCGH findings
Genomic position (bp)a
138,473,339 - 138,673,394
170,301,198 - 170,446,174
170,679,528 - 170,854,638
170,858,901 - 171,048,742
40,480,006 - 40,631,549
41,949,215 - 42,121,248
Oligobased array comparative genomic hybridization analysis
oaCGH analysis was performed using CytoChip Cancer 4x180K v2.0 (BlueGnome, Cambridge, UK) encompassing a 20 kb backbone with highest concentration of probes at 670 cancer genes. The analysis was done according to manufacturer's instructions using 0.5 µg patient DNA from bone marrow cells at initial diagnosis as described in . After hybridization, washing and drying the oligo array was scanned at 2.5 µm with GenePix 4400A microarray scanner. Initial analysis and normalization was done with BlueFuseMulti v2.6. For analysis and visualization normalized log2 probe signal values were imported into Nexus Copy Number software v. 6.1 (BioDiscovery, California, USA) and segmented using FASST2 segmentation algorithm with a minimum of 3 probes/segment. Regions of gain or loss contained within copy number variable regions (CNVs) were discarded. Reference genome was NCBI build 36.1 (hg18). Bioinformatics analysis was performed by querying the UCSC database (http://genome.ucsc.edu).
The study conforms to the provisions of the Declaration of Helsinki. Written informed consent was obtained from the patient. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Bacterial artificial chromosomes
World Helath Organization
The biotechnologists Bente Madsen and Pia Kristensen are greatly thanked for excellent technical assistance. The Danish Cancer Society supported the study.
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