research paper
Jumping translocations, a novel finding in chronic lymphocytic leukaemia
Cecelia R. Miller,1,2 Deborah Stephens,1,3 Amy S. Ruppert,1 Frederick Racke,4 Andrew McFaddin,3 Heather Breidenbach,4 Huey-Jen Lin,2 Kathy Waller,2 Tammy Bannerman,2 Jeffrey A. Jones,1,3 Jennifer A. Woyach,1,3 Leslie A. Andritsos,1,3 Kami Maddocks,1,3 Weiqiang Zhao,4 Gerard Lozanski,4 Joseph M. Flynn,1,3 Michael Grever,1,3 John C. Byrd1,3,5 and Nyla A. Heerema4 1
Division of Hematology, Department of Internal Medicine, The Ohio State University, 2Division of Medical Laboratory Science, School of Health and Rehabilitation, The Ohio State University, 3
Comprehensive Cancer Center, The Ohio State
University, 4Department of Pathology, The Ohio State University, and 5Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA Received 22 November 2014; accepted for
Summary A jumping translocation (JT) is a rare cytogenetic aberration that can occur in haematological malignancy. It involves the translocation of the same fragment of donor chromosome onto two or more recipient chromosomes, typically in different cells. In this study, we describe the first series of chronic lymphocytic leukaemia (CLL) patients with JTs reported to date. Following a review of 878 CLL patient karyotypes, we identified 26 patients (3%) with 97 JTs. The most commonly occurring breakpoint in these translocations was 17p11.2. Loss of TP53 was identified prior to or at the same time as JT in 23 of 26 patients (88%). All patients eventually developed a complex karyotype. All but one patient has required treatment for CLL, with estimated median time to treatment of 115 months. This study establishes JTs as a recurrent abnormality found in CLL patients with aggressive disease. JTs contribute to complex karyotypes and, in many cases, are involved in chromosomal rearrangements that result in loss of the tumour suppressor gene TP53. Keywords: chronic lymphocytic leukaemia, chromosomal rearrangement, cancer cytogenetics, complex karyotype, TP53.
publication 16 February 2015 Correspondence: Nyla A. Heerema, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA. E-mail: [email protected]
A jumping translocation (JT) is a rare cytogenetic aberration defined by translocations involving the same fragment of chromosome, called the donor chromosome, and two or more different recipient chromosomes in different cells in the same patient (Lejeune et al, 1979). In previous reports, donor chromosome breakpoints predominately occur in centromeric and heterochromatic regions, while recipient chromosome breakpoints frequently occur in telomeric and subtelomeric regions. The most commonly detected donor chromosome segment is 1q (Berger & Bernard, 2007). Other donor chromosomes have been described, including chromosomes 3, 7, 9, 11 and 17 (Reis et al, 1991; Wlodarska et al, 1994; Najfeld et al, 1995; Fan et al, 2000; Haltrich et al, 2006). The recipient chromosome appears to be random. Jumping translocations have been associated with aggressive disease and poor prognosis in various haematological First published online 19 April 2015 doi: 10.1111/bjh.13422
malignancies (Najfeld et al, 1995, 2010; Manola et al, 2008). They occur most frequently in multiple myeloma followed by acute lymphoblastic leukaemia and acute myeloid leukaemia (Berger & Bernard, 2007). To our knowledge, only a single mention of this phenomenon occurring in a chronic lymphocytic leukaemia (CLL) patient has been reported (Callet-Bauchu et al, 1999). Chronic lymphocytic leukaemia is a clonal proliferation of neoplastic B lymphocytes. It is the most common adult leukaemia in the Western World with a clinical course that is highly variable. While many patients do not require treatment for years, others exhibit aggressive disease associated with a poor prognosis (Byrd et al, 2004; Chiorazzi et al, 2005). Chromosomal abnormalities identified by cytogenetic analysis are one important prognostic factor in the risk stratification of CLL (Dohner et al, 2000). Historically, ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
Jumping Translocations in CLL identification of chromosomal aberrations by traditional metaphase cytogenetics has been limited by the low mitotic activity of CLL cells in culture. The recent introduction of CpG oligodeoxynucleotides (CpG-ODN) to CLL cultures has significantly improved the ability to obtain informative karyotypic results from patients with CLL (Dicker et al, 2006; Muthusamy et al, 2011). In this study, we used metaphase chromosomal analysis to establish JTs as a type of recurrent chromosomal abnormality occurring in CLL. Here we present 26 CLL patients with karyotypes containing this abnormality.
Methods Patient sample and data collection Records of 878 patients seen at The Ohio State University (OSU) for a diagnosis of CLL by International Workshop on CLL (IWCLL) criteria (Hallek et al, 2008), who had submitted cytogenetic material between October 2007 and July 2011, were reviewed for karyotypes containing JTs. Each confirmed case with a JT during this time period was then retrospectively reviewed for clinicopathological data from the time of diagnosis up to May 2013. This study was conducted under an OSU Institutional Review-board approved protocol in accordance with the Declaration of Helsinki.
Conventional cytogenetic analyses Cytogenetics was performed as previously described (Muthusamy et al, 2011). Briefly, cells from bone marrow or peripheral blood (20 9 106 cells/ml) were incubated in RPMI 1640 medium (Fischer Scientific, Houston, TX, USA) with 2% L-Glutamine (Gibco Invitrogen, Carlsbad, CA, USA), supplemented with 20% fetal bovine serum (Hyclone Laboratories, Logan, TX, USA) and 2% penicillin and streptomycin (Gibco Invitrogen). The mitogens used included: pokeweed mitogen (PWM, 10 lg/ml; Sigma Aldrich, St. Louis, MO, USA), phorbol 12-myristate 13-acetate (PMA, 40 ng/ml; Sigma Aldrich) and CpG ODN 685 (20 lg/ml; synthesized by Sigma Aldrich). The mitogens were added to the cultures, and the cells were incubated for 72 h under standard laboratory conditions. All samples were harvested, fixed, G-banded using trypsin, and stained with Wright stain according to standard laboratory procedures. Twenty metaphases were completely analyzed whenever possible. Karyotypes were described following the ISCN 2009 standard (Shaffer et al, 2009) except that single cell abnormalities were reported when they demonstrated a JT.
Fluorescence in situ hybridization Fluorescence in situ hybridization (FISH) analysis was also performed on the mitogen-stimulated cultures. A FISH panel of probes for CLL (data not shown) was analyzed which ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
included TP53 (17p13.1) (Abbott Molecular, Des Plains, IL, USA). Hybridization was according to the manufacturer’s directions. Two hundred cells per probe were analysed, 100 by each of two independent observers. Each case was compared for consistency of FISH results with conventional karyotyping results. Additionally, FISH using centromere probes (Abbott Molecular) was performed on metaphases in a subset of patients to confirm dicentric chromosomes.
Statistical methods Characteristics of patients who had been identified with JTs are described with frequencies and proportions for categorical variables and with medians and ranges for continuous variables. Time to treatment (TTT) was calculated from the date of diagnosis until the date of first treatment, censoring one patient who had not yet started treatment at last follow-up. Overall survival (OS) was calculated from the time of diagnosis until the date of death, censoring patients who were alive at last follow-up. TTT and OS estimates were calculated by the Kaplan–Meier method (Kaplan & Meier, 1958).
Results Clinical characteristics A total of 26 patients with JTs were identified among 878 CLL patients (30%, 95% confidence interval [CI]: 19–43%) seen over a period of 375 years. Clinically, this group of 26 patients (58% male) followed an aggressive disease course, with high-risk cytogenetics developing in all patients. At diagnosis of CLL in this patient cohort, the median age was 54 years (range: 37–77), with approximately 90% of the patients with Rai Stage 2 or less (Rai et al, 1975). Of the 16 patients with IGHV data available, 11 (69%) had IGHV-unmutated disease. The estimated median TTT was 115 months (95% CI: 30–256 months) (Fig 1), and all but one patient with 28 months of follow-up had begun treatment. The one patient without treatment is male, diagnosed at age 60 years with a Rai Stage of 0, but has since been re-staged to Rai Stage 2 and has been identified as also harbouring, in addition to a JT, del(17p) with a complex karyotype and unmutated IGHV disease. With a median follow-up of 83 months for the JT patients, there have been 13 deaths; the estimated OS at 6 years from CLL diagnosis was 66% (95% CI: 042–082) (Fig 1). At the time of JT detection, the median age was 61 years (range: 39–78) and 73% of patients had a Rai Stage of 3 or 4. In patients where CD38 and beta-2 microglobulin (b2m) data were available (n = 23 and n = 20, respectively), 39% of patients were positive for CD38 expression (defined as ≥20%) and 35% of patients had elevated b2m (≥4 mg/l). Cytogenetically, 23 of the 26 patients (88%) had del(17p). del(17p) was previously seen in 6 of 26 patients prior to 201
C. R. Miller et al 3 had stable disease, and 7 had progressive disease. Four patients progressed to Richter syndrome, all on or after the sample date when the JT was identified.
Jumping translocation characteristics
Fig 1. Time to treatment and overall survival probabilities for chronic lymphocytic leukaemia patients with jumping translocations. The estimated median time to treatment was 115 months and the estimated overall at 6 years from diagnosis was 66%.
detection of JT; loss of 17p occurred from several years before JT to less than a year before JT developed. All patients eventually developed a complex karyotype, defined as at least three independent aberrations, with 24 of 26 (92%) having at least five independent aberrations (Table SI). del(17p) occurred in 21% (181/878) of the overall CLL patient population at our institution at the time of this study. JT patients comprised 13% (23/181) of the del(17p) population. Complex karyotype was found in 33% (289/878) of patients; JT patients were 9% (26/289) of this population. Data regarding JTs at the time of diagnosis was limited for these cases. Karyotypes were available for only four patients within 3 months of diagnosis; of these, JTs were detected in three patients. One of these patients had not received any treatment for CLL and did not begin treatment for more than a year following identification of JT. The second patient had received one cycle of fludarabine prior to the identification of JT. The third patient previously received bortezomib and rituximab for an incorrect diagnosis of Waldenstr€ om macroglouninaemia at the time of CLL diagnosis and prior to JT identification. Not including the patient treated for Waldenstr€ om macroglouninaemia, there were a total of five patients (19%) with a JT in samples obtained prior to any CLL therapy. In the remaining 20 patients who had been treated prior to discovery of JT, the median number of therapies was three, with a range of 1–7. Following detection of JT, all but two patients have received some form of treatment. Response to first treatment following identification of JT included five patients with complete remissions; one with allogenic stem cell transplant, one with rituximab, doxorubicin, etoposide, vincristine, cyclophosphamide and prednisone (REPOCH), one with fludarabine, cyclophosphamide and rituximab (FCR), one on a clinical trial with cyclophosphamide, flavopiridol and rituximab, and one on a clinical trial with flavopiridol. Of the remaining 19 patients who received subsequent treatment; 9 had partial response, 202
Among the 26 cases, there were a total of 97 JTs. Examples of JTs in CLL patients are shown in Fig 2; complete karyotypes are provided in Table SI. Twenty-three patients had unbalanced JTs and two patients (Cases 6 and 16) had both balanced and unbalanced JTs. One patient (Case 2) exhibited a balanced JT as the sole abnormality, which is considered a very rare occurrence (Rosenwald et al, 1999; Fan et al, 2000). Serial cytogenetic samples were available for 22 of the 26 patients. In these serial samples JTs were detected in the first cytogenetic analysis performed at our institution in 12 patients. JTs were absent in the initial cytogenetic analysis in 10 patients; 6 of these patients initially had normal karyotypes, 1 patient had a single cytogenetic abnormality and 3 patients had complex karyotypes. Among the 26 patient samples, a total of 33 donor chromosomes were identified. For analysis purposes, we separated the JTs according to the localization of the donor chromosome breakpoints. Strikingly, 16 (48%) of the donor breakpoints occurred in the centromeric region 17p11.2 (Table I), whereas the other 17 occurred in at least 11 different chromosomes and have been classified as miscellaneous donor breakpoints (Table II). In this miscellaneous group, two repeat donor breakpoints were identified, one involving 4q12 and the other involving 18p11.2. Additional donor breakpoints were found at 1p32, 8p21, 9q12, 11q21, 12p11.2, 13p11.2, 13q14, 13q21, 14p11.2, 15p11.2 and 19p13.3; two breakpoints were of unidentified chromatin. Thus, of the 17 miscellaneous donor chromosomes not involving 17p11.2, 9 breakpoints (53%) occurred in centromeric regions, 6 (35%) occurred between the pericentromeric and subtelomeric regions and 2 (12%) were not identified. Across both donor breakpoint groups, seven patients (Cases 3, 7, 8, 17, 18, 23 and 25) had two unique donor chromosomes involved in JTs at the same time (Case 3 shown in Fig 2). Four of these seven patients with two unique donor chromosomes had a chromosome acting as both a donor and recipient in the JTs. Among the group of 16 donor chromosomes with breakpoints at 17p11.2, there were a total of 51 recipient chromosomes (Table I). The majority of recipient breakpoint locations occurred in centromeric regions (n = 35, 69%), with fewer occurring, respectively, between the pericentromeric and subtelomeric regions (n = 8, 16%) and within the subtelomeric region (n = 2, 4%); six (12%) of the recipient breakpoints were unknown. These JTs resulted in the formation of 36 dicentric chromosomes and two pseudodicentric chromosomes, most with recipient breakpoints near centromeres. Multiple repeat recipient breakpoint locations, all from centromeric regions, were identified in this group and included 18p11.2 (n = 7), 8p11.2 (n = 3), 14p11.2 (n = ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
Jumping Translocations in CLL
(A)
(B)
(C)
Fig 2. Partial karyotypes showing jumping translocations in chronic lymphocytic leukaemia. Arrows indicate breakpoint locations. (A) Jumping translocations (JTs) from Case 2 with balanced JTs showing t(1;3)(p32;q21), t(1;4)(p32;q28), t(1;14)(p32;q24) and t(1;22)(p32;q13). (B) JTs from Case 3 with both 17p11.2 and 14p11.2 acting as both donor and recipient breakpoints. The first JT has 17p11.2 as a donor breakpoint (top) translocating to form the dicentric chromosomes dic(13;17)(p11.2;p11.2), dic(14;17)(p11.2;p11.2), dic(17;18)(p11.2;p11.2) and dic(17;20)(p11.2; q13.3). The second JT in this patient has the 14p11.2 recipient breakpoint from the first JT now acting as a donor breakpoint (bottom), translocating to form the dicentric chromosomes dic(14;17)(p11.2;p11.2) and dic(14;22)(p11.2;p11.2). (C) JT from Case 10 showing dicentric chromosomes idic(17)(p11.2) and dic(17;18)(p11.2;p11.2).
3), 21p11.2 (n = 3), 17p11.2 (n = 2), 6p11.2 (n = 2), 8q11.2 (n = 2), 12p11.2 (n = 2) and 20p11.2 (n = 2). Among the group of 17 miscellaneous donor chromosomes, a total of 50 recipient chromosomes were identified. In contrast with what was found when 17p11.2 was the donor breakpoint, the recipient breakpoint locations associated with non-17p11.2 donors were more often found between the pericentromeric and subtelomeric regions or within the subtelomeric region, but less often in centromeric regions (P < 00001, Fisher’s exact test). Specifically, only 7 breakpoints (14%) involved centromeric regions, whereas 19 (38%) and 18 (36%) were involved between the pericentroª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
meric and subtelomeric regions or within the subtelomeric region, respectively; six (12%) of the recipient breakpoints were unknown. There were only eight unique dicentric or pseudodicentric chromosomes. Repeat recipient breakpoint locations in the miscellaneous group were found at chromosome bands 5q35 (n = 2), 12q24.1 (n = 2), 17p11.2 (n = 2) and 18q23 (n = 2).
Discussion Here we describe the first series of JTs occurring in CLL and provide evidence that this is a recurring event in this disease. 203
C. R. Miller et al Table I. Jumping translocation breakpoints for the 17p11.2 donor chromosome group.
Table II. Jumping translocation breakpoints for the miscellaneous donor chromosome group.
Case
Donor breakpoint
Recipient breakpoint
Case
Donor breakpoint
Recipient breakpoint
1
17p11.2*
2
1p32
3
17p11.2*
4q21 8q11.2* 16p11.2*,‡ 13p11.2*,‡ 20q13.3†,‡ 14p11.2*,‡ 18p11.2*,‡ 9q12*,‡ Unknown Unknown 18p11.2*,‡ 18p11.2*,‡ 8q21 Unknown 21p11.2*,‡ 18p11.2*,‡ 17p11.2*,‡ 18p11.2*,‡ 8p21§ 20p11.2*,‡ 4p12*,‡ 14p11.2*,‡ 17p11.2*,‡ 7q36†,‡ 6p11.2*,‡ Unknown 3p13§ 12p11.2*,‡ 18p11.2*,‡ 8q11.2* 15q15 6p11.2*,‡ 21p11.2*,‡ 14p11.2*,‡ 20p11.2*,‡ 8p11.2*,‡ Unknown 8p11.2*,‡ 12p11.2*,‡ 22p11.2*,‡ 18p11.2*,‡ 15p11.2*,‡ 21p11.2*,‡ 11q21 Unknown 4q25 11q13‡ 6q12*,‡ 19p12*,‡ 17p11.2*,‡ 8p11.2*,‡
3
14p11.2*
4
4q12*
5
Unknown
6
13q14
7
9q12*
8
Unknown
12
12p11.2*
15
18p11.2*
17
19p13.3
18
13p11.2*
3q21 4q28 14q24 22q13† 17p11.2*,‡ 22p11.2*,‡ 11q13 17q25† 18q23† 21q22† 8q24.3† 11q25† 18q23† 12q24.1 1q42 4q31 8p23 12q24.1 6q22 3q27 17p11.2*,‡ 1q44† 6p26† 12p13† 14q32† 5q35† 7q36† 11q24 Xq26 Unknown‡ Unknown‡ 10q26†,‡ 14p11.2*,‡ Unknown Unknown 5p13§ 18p11.2*,‡ 13p11.2*,‡ Unknown 3p21§ 1p21 Unknown 4q33 12q15 17p11.2* 3q29† 2q21 18p11.3†,‡ 5q35† 9q34†
7
17p11.2*
8
17p11.2*
9
17p11.2*
10
17p11.2*
11
17p11.2*
13
17p11.2*
14
17p11.2*
16
17p11.2*
17
17p11.2*
20
17p11.2*
21
17p11.2*
23
17p11.2*
24
17p11.2*
25
17p11.2*
Bold, repeat breakpoint location across all jumping translocations identified in chronic lymphocytic leukaemia. *Centromeric breakpoint. †Telomeric breakpoint. ‡Dicentric chromosome. §Pseudodicentric chromosome.
204
18p11.2* 19
8p21
22
13q21
23
11q21
25
15p11.2*
26
4q12*
Bold, repeat breakpoint location across all jumping translocations identified in chronic lymphocytic leukaemia. *Centromeric breakpoint. †Telomeric breakpoint. ‡Dicentric chromosome. §Pseudodicentric chromosome. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
Jumping Translocations in CLL We present 26 cases from a population of 878 patients seen at our institution. This subset represents approximately 3% of our patient population, which is comparable to the frequency of this abnormality seen in multiple myeloma, the most commonly reported haematological malignancy with JTs (Sawyer et al, 1998; Berger & Bernard, 2007). However, the prevalence of this abnormality in our patient population may be slightly underestimated due to the difficulties in detecting JTs that appear as rare non-clonal abnormalities. Our patient population is indicative of a large regional quaternary care centre, and patients tend to be at a later stage of their disease at presentation to our institution than the average CLL patient. The frequency of del(17p) in our patient population during the course of this study was 21% and that of a complex karyotype was 33%. As most patients present to outside facilities at their initial CLL diagnosis, we have limited data on the patient’s initial karyotype and frequently only FISH analysis was previously performed. Due to this, we are unable to determine the timing of JT development in 13 patients. For the other 13 patients, JTs were detected in three of the four patients with karyotypes performed within 3 months of diagnosis. In 10 patients for whom serial cytogenetic samples were available, including the one patient without a JT at diagnosis, JTs did not occur until later in the course of their disease. Our ability to identify multiple JTs is probably due to enhanced detection of chromosomal abnormalities by conventional chromosome analysis with the use of CpG-ODN to increase mitotic activity of CLL cells in culture (Heerema et al, 2010; Muthusamy et al, 2011). Using only FISH analysis, in place of metaphase cytogenetics in CLL, cannot detect these abnormalities and their associated karyotypic complexity. The majority of patients with CLL who were known to have a JT at some point during the course of their disease appeared to have an aggressive disease course. Twenty-five of the 26 patients had begun treatment, with an estimated TTT of 115 months. Twenty-three patients (88%) showed loss of TP53 by either FISH or karyotype analysis during the course of their disease. This loss occurred prior to or concurrently with the JT. TP53 is involved in arresting the cell cycle or inducing apoptosis in damaged cells (Vogelstein et al, 2000). Loss of TP53 in CLL patients is associated with increased drug resistance and shortened progression-free and overall survival (Dohner et al, 1995; Dohner et al, 2000; Byrd et al, 2006; Grever et al, 2007). This loss may also lead to genomic instability, causing patients to develop a greater number of chromosome abnormalities compared to cases with normal 17p (Haferlach et al, 2007). JTs occurred in three patients with no loss of TP53; however, the TP53 mutational status of these patients is not known. Loss of TP53 may provide a permissive environment for JTs to develop. Alternatively, additional factors not yet understood may also contribute. While data regarding JT breakpoints across all haematological malignancies are highly heterogeneous, certain trends have emerged. Breakpoints of donor chromosomes most ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
often occur in centromeric regions and heterochromatic regions, with a preference towards 1q. JTs involving 1q often result in partial trisomy. No recipient chromosome has been reported to have preferential involvement in these translocations. However, JT recipient breakpoints have been found most often in telomeric regions (Berger & Bernard, 2007). JTs in CLL contrasted with these trends in a number of ways. While the majority of donor breakpoints were centromeric (76%), heterochromatic breakpoints were rare. We found no donor breakpoints at 1q; instead repeat donor breakpoints were seen most commonly at 17p11.2, followed by 18p11.2 and 4q12. These translocations frequently resulted in partial monosomy. Across all donor and recipient chromosomes in CLL JTs, 16 repeat breakpoints were seen. Multiple repeat recipient breakpoints, particularly within the 17p11.2 donor group, suggest that contrary to other haematological malignancies (Berger & Bernard, 2007) recipient breakpoint locations in CLL JTs may not be entirely random nor do they favour telomeric breakpoints. Twelve of the repeat breakpoint locations occurred in chromatin directly adjacent to centromeres. The most frequent recipient breakpoint, 18p11.2, occurred eight times. Recipient breakpoint locations in CLL were significantly different (P < 00001) when comparing the 17p11.2 donor group (Table I) to the miscellaneous donor group (Table II). When associating with the 17p11.2 donor breakpoint, recipient breakpoints most often occurred in centromeric regions and very rarely in telomeric regions. Recipient breakpoints associated with the other donor chromosomes occurred between the pericentromeric and subtelomeric regions and in subtelomeric regions at similar rates, while centromeric breakpoints were less frequent. It is tempting to speculate that the mechanism behind JTs with 17p11.2 donor breakpoints may differ from other donor breakpoints. A total of 16 of the 33 donor chromosome breakpoints occurred at 17p11.2 (48%), indicating a preferential involvement of this band as a donor breakpoint for JTs in CLL. Multiple breakpoint cluster regions have been identified in the centromeric region of 17p (Scheurlen et al, 1999; Fink et al, 2006). The 17p11.2 region is characterized by multiple large palindromic low copy repeats (LCR) which may favour its increased involvement in rearrangements (Barbouti et al, 2004). LCRs are heavily represented in pericentromeric and subtelomeric regions and may result in unstable genomic regions that are prone to nonallelic homologous recombination (Stankiewicz & Lupski, 2002). LCRs have been proposed as target regions for JTs in a constitutional case (Stankiewicz et al, 2003). These characteristics of the 17p11.2 region, as well as its prevalence as a recurrent rearrangement site in CLL, provide a basis for its increased involvement in JTs in CLL. Jumping translocation involving 17p11.2 as a donor breakpoint resulted in the formation of dicentric or pseudodicentric chromosomes 75% of the time. In addition, in 3 of the 10 cases with only a miscellaneous donor chromosome, dicentric 205
C. R. Miller et al chromosomes with 17p11.2 breakpoints occurred without being involved in a JT (Table SI). These translocations resulted in loss of TP53 for these patients. Sawyer et al (2014) described the loss of TP53 via JTs in multiple myeloma with 17p acting as a recipient chromosome. In contrast, in CLL we identified 17p as a frequent donor chromosome. Loss of TP53 in CLL is commonly due to rearrangements involving 17p11.2 (Fink et al, 2006). Dicentric chromosomes involving 17p11, most frequently dicentric (17;18), have been previously reported as a recurrent abnormalities in CLL (Callet-Bauchu et al, 1999; Woyach et al, 2010). JTs appear to be another recurring type of rearrangement in CLL involving this region. Chromosome instability due to the presence of two centromeres in dicentric chromosomes may promote the development of JTs. In summary, our findings suggest that JTs are a type of recurrent abnormality occurring in CLL, often in conjunction with dicentric chromosomes involving 17p. These JTs appear to behave non-randomly; sequence homology between the repetitive elements in centromeric and telomeric regions as well as other regions containing LCR may mediate these translocations. Jumping translocations in CLL commonly occur in a complex karyotype, are frequently seen in patients with loss of TP53 and may directly contribute to this loss in many cases. Both complex karyotype and loss of TP53 are poor prognostic indicators in CLL. Patients who developed JTs developed disease at an earlier age than the average CLL population (Howlader et al, 2014) and required treatment relatively quickly. Of the 26 patients with JTs, four (15%) progressed to Richter transformation, which is slightly higher than in the average CLL population (Jain & O’Brien, 2012). In total, these patients with JTs in CLL had poor clinical outcomes; though whether this was due to the complex karyotype, loss of TP53, the JT or a combination of these factors is not clear. Therefore, further prospective investigation into
References Barbouti, A., Stankiewicz, P., Nusbaum, C., Cuomo, C., Cook, A., Hoglund, M., Johansson, B., Hagemeijer, A., Park, S.S., Mitelman, F., Lupski, J.R. & Fioretos, T. (2004) The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. American Journal of Human Genetics, 74, 1–10. Berger, R. & Bernard, O.A. (2007) Jumping translocations. Genes, Chromosomes & Cancer, 46, 717–723. Byrd, J.C., Stilgenbauer, S. & Flinn, I.W. (2004) Chronic lymphocytic leukemia. American Society of Hematology Educational Program Book, 1, 163–183. Byrd, J.C., Gribben, J.G., Peterson, B.L., Grever, M.R., Lozanski, G., Lucas, D.M., Lampson, B., Larson, R.A., Caligiuri, M.A. & Heerema, N.A.
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the mechanisms behind JT formation and their clinical consequences is warranted.
Acknowledgements We thank Dr. Lynne Abruzzo for reviewing the manuscript. CRM is supported by a training grant from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM068412. This work was supported by Specialized Center of Research from the Leukemia and Lymphoma Society, P50-CA140158, and The D. Warren Brown Foundation, Four Winds Foundation, The Sullivan Chronic Lymphocytic Leukemia Research Fund, Mr and Mrs Michael Thomas and Harry Mangurian Foundation.
Author contributions CRM, NAH, TB, KW, HLJ and JCB designed the study. CRM wrote the manuscript. CRM, DS and ASR performed the research and analysed the data. CRM, NAH, DS, JCB, FR, AM, HB, JAJ, JAW, LAA, KM, WZ, GL, JMF and MG collected the data. All authors reviewed and approved the final version of the manuscript.
Conflict of interest The authors have no competing interests.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table SI. Karyotypes of patients with jumping translocations in CLL.
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207
Jumping translocations, a novel finding in chronic lymphocytic leukaemia
Cecelia R. Miller,1,2 Deborah Stephens,1,3 Amy S. Ruppert,1 Frederick Racke,4 Andrew McFaddin,3 Heather Breidenbach,4 Huey-Jen Lin,2 Kathy Waller,2 Tammy Bannerman,2 Jeffrey A. Jones,1,3 Jennifer A. Woyach,1,3 Leslie A. Andritsos,1,3 Kami Maddocks,1,3 Weiqiang Zhao,4 Gerard Lozanski,4 Joseph M. Flynn,1,3 Michael Grever,1,3 John C. Byrd1,3,5 and Nyla A. Heerema4 1
Division of Hematology, Department of Internal Medicine, The Ohio State University, 2Division of Medical Laboratory Science, School of Health and Rehabilitation, The Ohio State University, 3
Comprehensive Cancer Center, The Ohio State
University, 4Department of Pathology, The Ohio State University, and 5Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA Received 22 November 2014; accepted for
Summary A jumping translocation (JT) is a rare cytogenetic aberration that can occur in haematological malignancy. It involves the translocation of the same fragment of donor chromosome onto two or more recipient chromosomes, typically in different cells. In this study, we describe the first series of chronic lymphocytic leukaemia (CLL) patients with JTs reported to date. Following a review of 878 CLL patient karyotypes, we identified 26 patients (3%) with 97 JTs. The most commonly occurring breakpoint in these translocations was 17p11.2. Loss of TP53 was identified prior to or at the same time as JT in 23 of 26 patients (88%). All patients eventually developed a complex karyotype. All but one patient has required treatment for CLL, with estimated median time to treatment of 115 months. This study establishes JTs as a recurrent abnormality found in CLL patients with aggressive disease. JTs contribute to complex karyotypes and, in many cases, are involved in chromosomal rearrangements that result in loss of the tumour suppressor gene TP53. Keywords: chronic lymphocytic leukaemia, chromosomal rearrangement, cancer cytogenetics, complex karyotype, TP53.
publication 16 February 2015 Correspondence: Nyla A. Heerema, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA. E-mail: [email protected]
A jumping translocation (JT) is a rare cytogenetic aberration defined by translocations involving the same fragment of chromosome, called the donor chromosome, and two or more different recipient chromosomes in different cells in the same patient (Lejeune et al, 1979). In previous reports, donor chromosome breakpoints predominately occur in centromeric and heterochromatic regions, while recipient chromosome breakpoints frequently occur in telomeric and subtelomeric regions. The most commonly detected donor chromosome segment is 1q (Berger & Bernard, 2007). Other donor chromosomes have been described, including chromosomes 3, 7, 9, 11 and 17 (Reis et al, 1991; Wlodarska et al, 1994; Najfeld et al, 1995; Fan et al, 2000; Haltrich et al, 2006). The recipient chromosome appears to be random. Jumping translocations have been associated with aggressive disease and poor prognosis in various haematological First published online 19 April 2015 doi: 10.1111/bjh.13422
malignancies (Najfeld et al, 1995, 2010; Manola et al, 2008). They occur most frequently in multiple myeloma followed by acute lymphoblastic leukaemia and acute myeloid leukaemia (Berger & Bernard, 2007). To our knowledge, only a single mention of this phenomenon occurring in a chronic lymphocytic leukaemia (CLL) patient has been reported (Callet-Bauchu et al, 1999). Chronic lymphocytic leukaemia is a clonal proliferation of neoplastic B lymphocytes. It is the most common adult leukaemia in the Western World with a clinical course that is highly variable. While many patients do not require treatment for years, others exhibit aggressive disease associated with a poor prognosis (Byrd et al, 2004; Chiorazzi et al, 2005). Chromosomal abnormalities identified by cytogenetic analysis are one important prognostic factor in the risk stratification of CLL (Dohner et al, 2000). Historically, ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
Jumping Translocations in CLL identification of chromosomal aberrations by traditional metaphase cytogenetics has been limited by the low mitotic activity of CLL cells in culture. The recent introduction of CpG oligodeoxynucleotides (CpG-ODN) to CLL cultures has significantly improved the ability to obtain informative karyotypic results from patients with CLL (Dicker et al, 2006; Muthusamy et al, 2011). In this study, we used metaphase chromosomal analysis to establish JTs as a type of recurrent chromosomal abnormality occurring in CLL. Here we present 26 CLL patients with karyotypes containing this abnormality.
Methods Patient sample and data collection Records of 878 patients seen at The Ohio State University (OSU) for a diagnosis of CLL by International Workshop on CLL (IWCLL) criteria (Hallek et al, 2008), who had submitted cytogenetic material between October 2007 and July 2011, were reviewed for karyotypes containing JTs. Each confirmed case with a JT during this time period was then retrospectively reviewed for clinicopathological data from the time of diagnosis up to May 2013. This study was conducted under an OSU Institutional Review-board approved protocol in accordance with the Declaration of Helsinki.
Conventional cytogenetic analyses Cytogenetics was performed as previously described (Muthusamy et al, 2011). Briefly, cells from bone marrow or peripheral blood (20 9 106 cells/ml) were incubated in RPMI 1640 medium (Fischer Scientific, Houston, TX, USA) with 2% L-Glutamine (Gibco Invitrogen, Carlsbad, CA, USA), supplemented with 20% fetal bovine serum (Hyclone Laboratories, Logan, TX, USA) and 2% penicillin and streptomycin (Gibco Invitrogen). The mitogens used included: pokeweed mitogen (PWM, 10 lg/ml; Sigma Aldrich, St. Louis, MO, USA), phorbol 12-myristate 13-acetate (PMA, 40 ng/ml; Sigma Aldrich) and CpG ODN 685 (20 lg/ml; synthesized by Sigma Aldrich). The mitogens were added to the cultures, and the cells were incubated for 72 h under standard laboratory conditions. All samples were harvested, fixed, G-banded using trypsin, and stained with Wright stain according to standard laboratory procedures. Twenty metaphases were completely analyzed whenever possible. Karyotypes were described following the ISCN 2009 standard (Shaffer et al, 2009) except that single cell abnormalities were reported when they demonstrated a JT.
Fluorescence in situ hybridization Fluorescence in situ hybridization (FISH) analysis was also performed on the mitogen-stimulated cultures. A FISH panel of probes for CLL (data not shown) was analyzed which ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
included TP53 (17p13.1) (Abbott Molecular, Des Plains, IL, USA). Hybridization was according to the manufacturer’s directions. Two hundred cells per probe were analysed, 100 by each of two independent observers. Each case was compared for consistency of FISH results with conventional karyotyping results. Additionally, FISH using centromere probes (Abbott Molecular) was performed on metaphases in a subset of patients to confirm dicentric chromosomes.
Statistical methods Characteristics of patients who had been identified with JTs are described with frequencies and proportions for categorical variables and with medians and ranges for continuous variables. Time to treatment (TTT) was calculated from the date of diagnosis until the date of first treatment, censoring one patient who had not yet started treatment at last follow-up. Overall survival (OS) was calculated from the time of diagnosis until the date of death, censoring patients who were alive at last follow-up. TTT and OS estimates were calculated by the Kaplan–Meier method (Kaplan & Meier, 1958).
Results Clinical characteristics A total of 26 patients with JTs were identified among 878 CLL patients (30%, 95% confidence interval [CI]: 19–43%) seen over a period of 375 years. Clinically, this group of 26 patients (58% male) followed an aggressive disease course, with high-risk cytogenetics developing in all patients. At diagnosis of CLL in this patient cohort, the median age was 54 years (range: 37–77), with approximately 90% of the patients with Rai Stage 2 or less (Rai et al, 1975). Of the 16 patients with IGHV data available, 11 (69%) had IGHV-unmutated disease. The estimated median TTT was 115 months (95% CI: 30–256 months) (Fig 1), and all but one patient with 28 months of follow-up had begun treatment. The one patient without treatment is male, diagnosed at age 60 years with a Rai Stage of 0, but has since been re-staged to Rai Stage 2 and has been identified as also harbouring, in addition to a JT, del(17p) with a complex karyotype and unmutated IGHV disease. With a median follow-up of 83 months for the JT patients, there have been 13 deaths; the estimated OS at 6 years from CLL diagnosis was 66% (95% CI: 042–082) (Fig 1). At the time of JT detection, the median age was 61 years (range: 39–78) and 73% of patients had a Rai Stage of 3 or 4. In patients where CD38 and beta-2 microglobulin (b2m) data were available (n = 23 and n = 20, respectively), 39% of patients were positive for CD38 expression (defined as ≥20%) and 35% of patients had elevated b2m (≥4 mg/l). Cytogenetically, 23 of the 26 patients (88%) had del(17p). del(17p) was previously seen in 6 of 26 patients prior to 201
C. R. Miller et al 3 had stable disease, and 7 had progressive disease. Four patients progressed to Richter syndrome, all on or after the sample date when the JT was identified.
Jumping translocation characteristics
Fig 1. Time to treatment and overall survival probabilities for chronic lymphocytic leukaemia patients with jumping translocations. The estimated median time to treatment was 115 months and the estimated overall at 6 years from diagnosis was 66%.
detection of JT; loss of 17p occurred from several years before JT to less than a year before JT developed. All patients eventually developed a complex karyotype, defined as at least three independent aberrations, with 24 of 26 (92%) having at least five independent aberrations (Table SI). del(17p) occurred in 21% (181/878) of the overall CLL patient population at our institution at the time of this study. JT patients comprised 13% (23/181) of the del(17p) population. Complex karyotype was found in 33% (289/878) of patients; JT patients were 9% (26/289) of this population. Data regarding JTs at the time of diagnosis was limited for these cases. Karyotypes were available for only four patients within 3 months of diagnosis; of these, JTs were detected in three patients. One of these patients had not received any treatment for CLL and did not begin treatment for more than a year following identification of JT. The second patient had received one cycle of fludarabine prior to the identification of JT. The third patient previously received bortezomib and rituximab for an incorrect diagnosis of Waldenstr€ om macroglouninaemia at the time of CLL diagnosis and prior to JT identification. Not including the patient treated for Waldenstr€ om macroglouninaemia, there were a total of five patients (19%) with a JT in samples obtained prior to any CLL therapy. In the remaining 20 patients who had been treated prior to discovery of JT, the median number of therapies was three, with a range of 1–7. Following detection of JT, all but two patients have received some form of treatment. Response to first treatment following identification of JT included five patients with complete remissions; one with allogenic stem cell transplant, one with rituximab, doxorubicin, etoposide, vincristine, cyclophosphamide and prednisone (REPOCH), one with fludarabine, cyclophosphamide and rituximab (FCR), one on a clinical trial with cyclophosphamide, flavopiridol and rituximab, and one on a clinical trial with flavopiridol. Of the remaining 19 patients who received subsequent treatment; 9 had partial response, 202
Among the 26 cases, there were a total of 97 JTs. Examples of JTs in CLL patients are shown in Fig 2; complete karyotypes are provided in Table SI. Twenty-three patients had unbalanced JTs and two patients (Cases 6 and 16) had both balanced and unbalanced JTs. One patient (Case 2) exhibited a balanced JT as the sole abnormality, which is considered a very rare occurrence (Rosenwald et al, 1999; Fan et al, 2000). Serial cytogenetic samples were available for 22 of the 26 patients. In these serial samples JTs were detected in the first cytogenetic analysis performed at our institution in 12 patients. JTs were absent in the initial cytogenetic analysis in 10 patients; 6 of these patients initially had normal karyotypes, 1 patient had a single cytogenetic abnormality and 3 patients had complex karyotypes. Among the 26 patient samples, a total of 33 donor chromosomes were identified. For analysis purposes, we separated the JTs according to the localization of the donor chromosome breakpoints. Strikingly, 16 (48%) of the donor breakpoints occurred in the centromeric region 17p11.2 (Table I), whereas the other 17 occurred in at least 11 different chromosomes and have been classified as miscellaneous donor breakpoints (Table II). In this miscellaneous group, two repeat donor breakpoints were identified, one involving 4q12 and the other involving 18p11.2. Additional donor breakpoints were found at 1p32, 8p21, 9q12, 11q21, 12p11.2, 13p11.2, 13q14, 13q21, 14p11.2, 15p11.2 and 19p13.3; two breakpoints were of unidentified chromatin. Thus, of the 17 miscellaneous donor chromosomes not involving 17p11.2, 9 breakpoints (53%) occurred in centromeric regions, 6 (35%) occurred between the pericentromeric and subtelomeric regions and 2 (12%) were not identified. Across both donor breakpoint groups, seven patients (Cases 3, 7, 8, 17, 18, 23 and 25) had two unique donor chromosomes involved in JTs at the same time (Case 3 shown in Fig 2). Four of these seven patients with two unique donor chromosomes had a chromosome acting as both a donor and recipient in the JTs. Among the group of 16 donor chromosomes with breakpoints at 17p11.2, there were a total of 51 recipient chromosomes (Table I). The majority of recipient breakpoint locations occurred in centromeric regions (n = 35, 69%), with fewer occurring, respectively, between the pericentromeric and subtelomeric regions (n = 8, 16%) and within the subtelomeric region (n = 2, 4%); six (12%) of the recipient breakpoints were unknown. These JTs resulted in the formation of 36 dicentric chromosomes and two pseudodicentric chromosomes, most with recipient breakpoints near centromeres. Multiple repeat recipient breakpoint locations, all from centromeric regions, were identified in this group and included 18p11.2 (n = 7), 8p11.2 (n = 3), 14p11.2 (n = ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
Jumping Translocations in CLL
(A)
(B)
(C)
Fig 2. Partial karyotypes showing jumping translocations in chronic lymphocytic leukaemia. Arrows indicate breakpoint locations. (A) Jumping translocations (JTs) from Case 2 with balanced JTs showing t(1;3)(p32;q21), t(1;4)(p32;q28), t(1;14)(p32;q24) and t(1;22)(p32;q13). (B) JTs from Case 3 with both 17p11.2 and 14p11.2 acting as both donor and recipient breakpoints. The first JT has 17p11.2 as a donor breakpoint (top) translocating to form the dicentric chromosomes dic(13;17)(p11.2;p11.2), dic(14;17)(p11.2;p11.2), dic(17;18)(p11.2;p11.2) and dic(17;20)(p11.2; q13.3). The second JT in this patient has the 14p11.2 recipient breakpoint from the first JT now acting as a donor breakpoint (bottom), translocating to form the dicentric chromosomes dic(14;17)(p11.2;p11.2) and dic(14;22)(p11.2;p11.2). (C) JT from Case 10 showing dicentric chromosomes idic(17)(p11.2) and dic(17;18)(p11.2;p11.2).
3), 21p11.2 (n = 3), 17p11.2 (n = 2), 6p11.2 (n = 2), 8q11.2 (n = 2), 12p11.2 (n = 2) and 20p11.2 (n = 2). Among the group of 17 miscellaneous donor chromosomes, a total of 50 recipient chromosomes were identified. In contrast with what was found when 17p11.2 was the donor breakpoint, the recipient breakpoint locations associated with non-17p11.2 donors were more often found between the pericentromeric and subtelomeric regions or within the subtelomeric region, but less often in centromeric regions (P < 00001, Fisher’s exact test). Specifically, only 7 breakpoints (14%) involved centromeric regions, whereas 19 (38%) and 18 (36%) were involved between the pericentroª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
meric and subtelomeric regions or within the subtelomeric region, respectively; six (12%) of the recipient breakpoints were unknown. There were only eight unique dicentric or pseudodicentric chromosomes. Repeat recipient breakpoint locations in the miscellaneous group were found at chromosome bands 5q35 (n = 2), 12q24.1 (n = 2), 17p11.2 (n = 2) and 18q23 (n = 2).
Discussion Here we describe the first series of JTs occurring in CLL and provide evidence that this is a recurring event in this disease. 203
C. R. Miller et al Table I. Jumping translocation breakpoints for the 17p11.2 donor chromosome group.
Table II. Jumping translocation breakpoints for the miscellaneous donor chromosome group.
Case
Donor breakpoint
Recipient breakpoint
Case
Donor breakpoint
Recipient breakpoint
1
17p11.2*
2
1p32
3
17p11.2*
4q21 8q11.2* 16p11.2*,‡ 13p11.2*,‡ 20q13.3†,‡ 14p11.2*,‡ 18p11.2*,‡ 9q12*,‡ Unknown Unknown 18p11.2*,‡ 18p11.2*,‡ 8q21 Unknown 21p11.2*,‡ 18p11.2*,‡ 17p11.2*,‡ 18p11.2*,‡ 8p21§ 20p11.2*,‡ 4p12*,‡ 14p11.2*,‡ 17p11.2*,‡ 7q36†,‡ 6p11.2*,‡ Unknown 3p13§ 12p11.2*,‡ 18p11.2*,‡ 8q11.2* 15q15 6p11.2*,‡ 21p11.2*,‡ 14p11.2*,‡ 20p11.2*,‡ 8p11.2*,‡ Unknown 8p11.2*,‡ 12p11.2*,‡ 22p11.2*,‡ 18p11.2*,‡ 15p11.2*,‡ 21p11.2*,‡ 11q21 Unknown 4q25 11q13‡ 6q12*,‡ 19p12*,‡ 17p11.2*,‡ 8p11.2*,‡
3
14p11.2*
4
4q12*
5
Unknown
6
13q14
7
9q12*
8
Unknown
12
12p11.2*
15
18p11.2*
17
19p13.3
18
13p11.2*
3q21 4q28 14q24 22q13† 17p11.2*,‡ 22p11.2*,‡ 11q13 17q25† 18q23† 21q22† 8q24.3† 11q25† 18q23† 12q24.1 1q42 4q31 8p23 12q24.1 6q22 3q27 17p11.2*,‡ 1q44† 6p26† 12p13† 14q32† 5q35† 7q36† 11q24 Xq26 Unknown‡ Unknown‡ 10q26†,‡ 14p11.2*,‡ Unknown Unknown 5p13§ 18p11.2*,‡ 13p11.2*,‡ Unknown 3p21§ 1p21 Unknown 4q33 12q15 17p11.2* 3q29† 2q21 18p11.3†,‡ 5q35† 9q34†
7
17p11.2*
8
17p11.2*
9
17p11.2*
10
17p11.2*
11
17p11.2*
13
17p11.2*
14
17p11.2*
16
17p11.2*
17
17p11.2*
20
17p11.2*
21
17p11.2*
23
17p11.2*
24
17p11.2*
25
17p11.2*
Bold, repeat breakpoint location across all jumping translocations identified in chronic lymphocytic leukaemia. *Centromeric breakpoint. †Telomeric breakpoint. ‡Dicentric chromosome. §Pseudodicentric chromosome.
204
18p11.2* 19
8p21
22
13q21
23
11q21
25
15p11.2*
26
4q12*
Bold, repeat breakpoint location across all jumping translocations identified in chronic lymphocytic leukaemia. *Centromeric breakpoint. †Telomeric breakpoint. ‡Dicentric chromosome. §Pseudodicentric chromosome. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
Jumping Translocations in CLL We present 26 cases from a population of 878 patients seen at our institution. This subset represents approximately 3% of our patient population, which is comparable to the frequency of this abnormality seen in multiple myeloma, the most commonly reported haematological malignancy with JTs (Sawyer et al, 1998; Berger & Bernard, 2007). However, the prevalence of this abnormality in our patient population may be slightly underestimated due to the difficulties in detecting JTs that appear as rare non-clonal abnormalities. Our patient population is indicative of a large regional quaternary care centre, and patients tend to be at a later stage of their disease at presentation to our institution than the average CLL patient. The frequency of del(17p) in our patient population during the course of this study was 21% and that of a complex karyotype was 33%. As most patients present to outside facilities at their initial CLL diagnosis, we have limited data on the patient’s initial karyotype and frequently only FISH analysis was previously performed. Due to this, we are unable to determine the timing of JT development in 13 patients. For the other 13 patients, JTs were detected in three of the four patients with karyotypes performed within 3 months of diagnosis. In 10 patients for whom serial cytogenetic samples were available, including the one patient without a JT at diagnosis, JTs did not occur until later in the course of their disease. Our ability to identify multiple JTs is probably due to enhanced detection of chromosomal abnormalities by conventional chromosome analysis with the use of CpG-ODN to increase mitotic activity of CLL cells in culture (Heerema et al, 2010; Muthusamy et al, 2011). Using only FISH analysis, in place of metaphase cytogenetics in CLL, cannot detect these abnormalities and their associated karyotypic complexity. The majority of patients with CLL who were known to have a JT at some point during the course of their disease appeared to have an aggressive disease course. Twenty-five of the 26 patients had begun treatment, with an estimated TTT of 115 months. Twenty-three patients (88%) showed loss of TP53 by either FISH or karyotype analysis during the course of their disease. This loss occurred prior to or concurrently with the JT. TP53 is involved in arresting the cell cycle or inducing apoptosis in damaged cells (Vogelstein et al, 2000). Loss of TP53 in CLL patients is associated with increased drug resistance and shortened progression-free and overall survival (Dohner et al, 1995; Dohner et al, 2000; Byrd et al, 2006; Grever et al, 2007). This loss may also lead to genomic instability, causing patients to develop a greater number of chromosome abnormalities compared to cases with normal 17p (Haferlach et al, 2007). JTs occurred in three patients with no loss of TP53; however, the TP53 mutational status of these patients is not known. Loss of TP53 may provide a permissive environment for JTs to develop. Alternatively, additional factors not yet understood may also contribute. While data regarding JT breakpoints across all haematological malignancies are highly heterogeneous, certain trends have emerged. Breakpoints of donor chromosomes most ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 200–207
often occur in centromeric regions and heterochromatic regions, with a preference towards 1q. JTs involving 1q often result in partial trisomy. No recipient chromosome has been reported to have preferential involvement in these translocations. However, JT recipient breakpoints have been found most often in telomeric regions (Berger & Bernard, 2007). JTs in CLL contrasted with these trends in a number of ways. While the majority of donor breakpoints were centromeric (76%), heterochromatic breakpoints were rare. We found no donor breakpoints at 1q; instead repeat donor breakpoints were seen most commonly at 17p11.2, followed by 18p11.2 and 4q12. These translocations frequently resulted in partial monosomy. Across all donor and recipient chromosomes in CLL JTs, 16 repeat breakpoints were seen. Multiple repeat recipient breakpoints, particularly within the 17p11.2 donor group, suggest that contrary to other haematological malignancies (Berger & Bernard, 2007) recipient breakpoint locations in CLL JTs may not be entirely random nor do they favour telomeric breakpoints. Twelve of the repeat breakpoint locations occurred in chromatin directly adjacent to centromeres. The most frequent recipient breakpoint, 18p11.2, occurred eight times. Recipient breakpoint locations in CLL were significantly different (P < 00001) when comparing the 17p11.2 donor group (Table I) to the miscellaneous donor group (Table II). When associating with the 17p11.2 donor breakpoint, recipient breakpoints most often occurred in centromeric regions and very rarely in telomeric regions. Recipient breakpoints associated with the other donor chromosomes occurred between the pericentromeric and subtelomeric regions and in subtelomeric regions at similar rates, while centromeric breakpoints were less frequent. It is tempting to speculate that the mechanism behind JTs with 17p11.2 donor breakpoints may differ from other donor breakpoints. A total of 16 of the 33 donor chromosome breakpoints occurred at 17p11.2 (48%), indicating a preferential involvement of this band as a donor breakpoint for JTs in CLL. Multiple breakpoint cluster regions have been identified in the centromeric region of 17p (Scheurlen et al, 1999; Fink et al, 2006). The 17p11.2 region is characterized by multiple large palindromic low copy repeats (LCR) which may favour its increased involvement in rearrangements (Barbouti et al, 2004). LCRs are heavily represented in pericentromeric and subtelomeric regions and may result in unstable genomic regions that are prone to nonallelic homologous recombination (Stankiewicz & Lupski, 2002). LCRs have been proposed as target regions for JTs in a constitutional case (Stankiewicz et al, 2003). These characteristics of the 17p11.2 region, as well as its prevalence as a recurrent rearrangement site in CLL, provide a basis for its increased involvement in JTs in CLL. Jumping translocation involving 17p11.2 as a donor breakpoint resulted in the formation of dicentric or pseudodicentric chromosomes 75% of the time. In addition, in 3 of the 10 cases with only a miscellaneous donor chromosome, dicentric 205
C. R. Miller et al chromosomes with 17p11.2 breakpoints occurred without being involved in a JT (Table SI). These translocations resulted in loss of TP53 for these patients. Sawyer et al (2014) described the loss of TP53 via JTs in multiple myeloma with 17p acting as a recipient chromosome. In contrast, in CLL we identified 17p as a frequent donor chromosome. Loss of TP53 in CLL is commonly due to rearrangements involving 17p11.2 (Fink et al, 2006). Dicentric chromosomes involving 17p11, most frequently dicentric (17;18), have been previously reported as a recurrent abnormalities in CLL (Callet-Bauchu et al, 1999; Woyach et al, 2010). JTs appear to be another recurring type of rearrangement in CLL involving this region. Chromosome instability due to the presence of two centromeres in dicentric chromosomes may promote the development of JTs. In summary, our findings suggest that JTs are a type of recurrent abnormality occurring in CLL, often in conjunction with dicentric chromosomes involving 17p. These JTs appear to behave non-randomly; sequence homology between the repetitive elements in centromeric and telomeric regions as well as other regions containing LCR may mediate these translocations. Jumping translocations in CLL commonly occur in a complex karyotype, are frequently seen in patients with loss of TP53 and may directly contribute to this loss in many cases. Both complex karyotype and loss of TP53 are poor prognostic indicators in CLL. Patients who developed JTs developed disease at an earlier age than the average CLL population (Howlader et al, 2014) and required treatment relatively quickly. Of the 26 patients with JTs, four (15%) progressed to Richter transformation, which is slightly higher than in the average CLL population (Jain & O’Brien, 2012). In total, these patients with JTs in CLL had poor clinical outcomes; though whether this was due to the complex karyotype, loss of TP53, the JT or a combination of these factors is not clear. Therefore, further prospective investigation into
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Acknowledgements We thank Dr. Lynne Abruzzo for reviewing the manuscript. CRM is supported by a training grant from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM068412. This work was supported by Specialized Center of Research from the Leukemia and Lymphoma Society, P50-CA140158, and The D. Warren Brown Foundation, Four Winds Foundation, The Sullivan Chronic Lymphocytic Leukemia Research Fund, Mr and Mrs Michael Thomas and Harry Mangurian Foundation.
Author contributions CRM, NAH, TB, KW, HLJ and JCB designed the study. CRM wrote the manuscript. CRM, DS and ASR performed the research and analysed the data. CRM, NAH, DS, JCB, FR, AM, HB, JAJ, JAW, LAA, KM, WZ, GL, JMF and MG collected the data. All authors reviewed and approved the final version of the manuscript.
Conflict of interest The authors have no competing interests.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table SI. Karyotypes of patients with jumping translocations in CLL.
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