Jumping Translocations of 3q in Acute Promyelocytic Leukemia

Jumping Translocations of 3q in Acute Promyelocytic Leukemia Jacqueline R. Batanian, Cherie H. Dunphy, and Donna A. Wall

ABSTRACT: Jumping translocation is a rare phenomenon, seldom reported to occur in cancer. A complex four-way translocation involving chromosomes 3, 9, 15, and 17 was identified in the chromosome study on a patient with a history of an acute promyelocytic leukemia (APL). In the follow-up studies, the same complex rearrangement exhibited a jumping translocation between chromosomes 3 and 9 in one clone and 3 and 6 in another clone. This is the first reported case of jumping translocation in APL. © Elsevier Science Inc., 1998

INTRODUCTION Jumping translocation (JT) is a term used to describe the translocation of the same chromosome breakpoint to two or more different recipient chromosomes in different cell lines of the same patient [1]. Two types of JT have been described: constitutional [2] and acquired. Constitutional JT has been associated with normal [1, 3, 4] and abnormal phenotypes [2, 5], with chromosome 15 being the most frequently involved [6]. In acquired JT, however, the long arm of chromosome 1 has been a frequent finding, as seen in cases of leukemia [7] and lymphoma [8]. In lymphoma cases, JT was suggestive of a poor prognostic biological marker [9, 10]. To our knowledge, JT has never been identified in a case of acute promyelocytic leukemia (APL). Acute promyelocytic leukemia is characterized by hypergranular bone marrow morphology, the presence of disseminated intravascular coagulation, and a specific reciprocal translocation between the long arms of chromosomes 15 and 17 [11]. The breakpoints of the translocation occur within the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the putative transcription factor called myelo-gene or the better known promyelocytic leukemia (PML)-gene on chromosome 15 [12]. The chimeric gene (RARA-PML) has always been characteristic of APL morphology in simple variants [13–15], complex translo-

From the Department of Pediatrics (J. R. B., D. A. W.) and the Department of Pathology (J. R. B., C. H. D.), St. Louis University School of Medicine, and Cardinal Glennon Children’s Hospital (J. R. B., D. A. W.), St. Louis, Missouri, USA Address reprint requests to: Dr. J. R. Batanian, Department of Pediatrics, St. Louis University School of Medicine, Cardinal Glennon Children’s Hospital, 1465 South Grand Blvd., St. Louis, MO 63104. Received February 13, 1998; accepted May 26, 1998. Cancer Genet Cytogenet 108:149–153 (1999)  Elsevier Science Inc., 1998 655 Avenue of the Americas, New York, NY 10010

cations [16, 17], and negative cytogenetic results of t(15;17) [11, 18–20]. We report on one patient with a history of APL who had the t(15;17) in a complex translocation involving chromosome 3 with a jumping rearrangement between the short arm of chromosome 6 and the long arm of chromosome 9. This type of JT in a patient with PML, to our knowledge, has never been reported. CLINICAL FINDINGS The patient (LB) was diagnosed in March 1995 at 13 months of age with APL, presenting with leukocytosis, thrombocytopenia, and disseminated intravascular coagulopathy. The initial cytogenetics of the leukemia were a complex translocation involving 15 and 17. She failed to enter remission with two chemotherapy inductions ('1: daunomycin, Ara-C, 6-thioguanine followed by '2: high dose Ara-C). Oral transretinoic acid was started and she entered a morphologic and cytogenetic remission in July 1995. At that point, polymerase chain reaction (PCR) analysis continued to be positive for the rearranged retinoic receptor. In October 1995, she underwent an unrelated donor bone marrow transplant from a male donor. The preparation regimen utilized total body radiation and cyclophosphamide; the graft was not manipulated. She recovered well from transplant but bone marrow aspirate at day 1100 post bone marrow transplant (January 1996) demonstrated recurrent disease. Her immunosuppression was stopped and oral transretinoic acid therapy was started. She continued to have progressive disease. In April 1996, she presented to Cardinal Glennon Children’s Hospital in full relapse with more than 80% of marrow cells being blasts. After salvage chemotherapy (mitoxantrone, VP16, cyclosporine) failed to improve her condition, she was given intravenous liposomal retinoic acid and arsenic trioxide on a compassionate basis. After a

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Table 1 A summary of bone marrow chromosome and fluorescence in situ hybridization analyses

Date of analysis

Total number of abnormal cells/ analyzed cells

Karyotype of abnormal cells

Culture type

Fluorescence in situ hybridization using X- and Y-specific centromere probes

6/17/95

23/23

46,XX,t(3;9;17;15)(q21;q34;q11.2;q22), der(5)ins(5)(q14;q34q31)del(5)(q34)

24-hour

NA

2/21/96

19/20

46,XX,t(3;9;17;15)(q21;q34;q11.2;q22) [5]/46,idem,der(5)ins(5)(q14q34q31) del(5)(q34)[14]

DP, 24-hour, 48hour

NA

3/26/96

15/15

46,XX,t(3;9;17;15)(q21;q34;q11.2;q22), der(5)ins(5)(q14q34q31)del(5)(q34) [12]/46,idem,t(3;6;17;15)(q21;p23; q11.2;q22)[3]

24-hour

XX in 95/120 XY in 25/120

4/18/96

15/15

46,XX,t(3;9;17;15)(q21;q34;q11.2;q22), der(5)ins(5)(q14;q34q31)del(5)(q34) [13]/46idem,2der(15)[2]

24-hour, 96hour

XX in 90/92 XY in 2/92

5/3/96

15/15

46,XX,t(3;9;17;15)(q21;q34;q11.2;q22), der(5)ins(5)(q14;q34q31)del(5)(q34)

24-hour, 72hour

XX in 98/100 XY in 2/100

5/29/96

0 (Failure)

Failure of bone marrow culture growth

Failure

XX in 0/66 XY in 66/66

6/18/96

0/15

Chromosome analysis was not performed

—

XX in 0/100 XY in 100/100

Abbreviations: NA, not available; DP, direct preparation.

2-month period of aplasia, the child’s counts recovered and she entered morphologic, cytogenetic, and molecular remission. She received a further 1 year of liposomal retinoic acid therapy (three times a week) and has been off all therapy since July 1997. PATHOLOGY AND FLOW CYTOMETRY FINDINGS At the time of recurrence, the bone marrow aspirate showed a hypercellular marrow with increased (47%) blasts and atypical promyelocytes. Flow cytometric analysis of the bone marrow aspirate demonstrated a population of large cells (41%) with expression of CD13, CD33, C-kit (CD117) without associated expression of HLA-DR or CD34. CYTOGENETIC AND FISH FINDINGS Sixteen chromosome studies have already been performed on the patient bone marrow. Table 1 shows a summary of six studies, five of which followed first bone marrow transplant with an opposite sex donor. In the remaining 10 studies, fluorescence in situ hybridization (FISH) using X- and Y-specific centromere probes was the only cytogenetic testing performed. The pretreatment chromosome study showed a complex chromosomal rearrangement involving chromosomes 3, 9, 17, and 15 and a derivative 5 of undetermined origin. [46,XX,t(3;9;17;15)(q21;q34;q11.2;q22),der(5)ins(5)(q14; q34q31)del(5)(q34)]. The same complex translocation was identified in all cells examined the first four follow-up studies. In addition to the original abnormal clone, the study '3 revealed a JT of the long arm of chromosome 3

with either the terminal 9qter in 12/15 cells, or the terminal 6pter in 3/15 cells (Figs. 1 and 2). [46,XX,t(3;6;17;15)(q21;p23;q11.2;q22),der(5)ins(5)(q14; q34 q31)del(5)(q34)]. In both cell lines, chromosomes 15 and 17 remained part of the complex rearrangement besides the abnormal 5. The terminal dark band of chromosome 15 appeared to be translocated onto the derivative chromosome 3 (Figs. 1 and 3). In addition, the terminal band of chromosome 17 appeared to have either a light terminal band of 9qter (Figs. 1 and 3) or a dark band of 6pter (Fig. 2). Besides the complex translocation involving chromosomes 15 and 17, there was a clonal evolution in the form of a derivative (5) that appeared to have an inverted insertion of (5q) and a terminal deletion of the band q34.1. It is to be noted that the clonal abnormalities were identified in all different types of cultures including a direct preparation, 24-, 48-, and 72-hour cultures. Fluorescence in situ hybridization using specific painting probes of chromosomes 3, 5, 9, 15, and 17 was performed on G-banded bone marrow metaphases. The hybridization confirmed the G-banded complex karyotypes. The signals of painting probes were not, however, strong enough to capture using a regular camera. Fluorescence in situ hybridization using specific alpha satellite probes of chromosomes X and Y was performed to identify the percentage of donor (XY) versus patient (XX) cells. In the first four studies where routine cytogenetic tests showed the complex translocation, the FISH identified most cells to be of patient origin. When the routine cytogenetic study showed growth failure with zero metaphase, most interphase cells were from the donor. Since then, 10 FISH and standard cytogenetic studies indicate remission showing normal 46,XY (donor cells).

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Figure 1 A G-banding karyotype showing a four-way translocation involving chromosomes 3, 9, 15, and 17 and a derivative 5[46,XX,t(3;9;17;15)(q21;q34;q11.2q22),der(5)ins(5)(q14;q34q31)del(5)(q34).

DISCUSSION This case of APL had the characteristic rearrangement (15;17) involved in a complex JT. This type of translocation was first described in 1976 documenting constitutional acrocentric satellite movements in three generations [21]. An acquired abnormality of JT type was first reported 10 years later [22]. Since then, JTs and telomeric associations (TAS) became synonymous, although their mechanism and origin might be different. Unlike JT, TAS do not have a common chromosome donor in multiple related clones per one malignancy. This difference has also been discussed in Seghezzi et al. (1995) who identified JT in case of acute lymphoblastic leukemia (ALL) [7] and Vermeesch et al. (1997) [23] who studied telomeric sequences at the junction sites of JTs. Considering JT and TAS being different, JT is a rare phenomenon. Most acquired JT have been detected in B-cell disorders, with the long arm of chromosome 1 being the most commonly involved [10]. In the present case, the JT consisted of chromosome 3, which entailed a complex translocation involving chromosomes 6 or 9, 15, and 17. McKinney et al. [16] reported two cases of complex (15;17) translocation involving chromosome 3 with breakpoints on the short arm of chromosome 3 at band p12 and p21, respectively. No JT was identified in these two cases. In the present

case, the breakpoint of JT chromosome 3 was at band q21, which differs from 3q13.3, a breakpoint of another JT identified in a case of acute myeloid leukemia [20]. Both chromosomes 1 and 3 are frequently involved in multiple acquired rearrangements that are associated with specific hematological disorders [24]. This fact raises the questions of whether hot spot breakpoints in cancer are prone to unstable rearrangement in the form of JT. Different mechanisms have been proposed to explain the origin of constitutional JTs [2, 25]. It was suggested that JT could be the result of exchange between homologous regions of repetitive DNA located at the breakpoints [4], or due to the presence of interstitial telomeric sequences [23, 25]. In acquired diseases, however, the mechanism of JT could be different. Acquired JTs are frequently detected in the presence of specific gene rearrangement such as t(8;14) in ALL-L3 [7], t(14;18) in follicular lymphoma [26], and t(15;17) in APL (present case). The co-appearance of JT with specific rearrangements may suggest that JTs occur secondary to the primary clone and may result from a genome instability. This suggestion is supported by studies on SV40-transformed human fibroblasts [27] showing that JTs occur at early passages, with some of them giving rise to clonal rearrangements at late passages. This may explain the find-

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Figure 2 A G-banding karyotype showing a four-way translocation involving chromosomes 3, 6, 15, and 17 and a derivative 5[46,XX,t(3;6;17;15)(q21;p23;q11.2;q22),der(5)ins(5)(q14;q34q31)del(5)(q34).

ing of JT in premalignant cases [28] that eventually lead to clonal imbalanced JT in advanced malignant tumors [29]. Furthermore, studies on transformed human fibroblasts SV-40 showed that destabilization of karyotype due to transfection may cause a JT [30] in order to stabilize the human genome as seen in a human immunodeficiency virus-related non-Hodgkin lymphoma case. In this case, JT

Figure 3. A partial G-banding karyotype showing a four-way translocation at 550 band resolution. Although, the order of translocated chromosomal segments is 3 → 9 → 17 → 15. Chromosome pair (15) is positioned next to chromosome pair (3) to provide an unequivocal visual comparison between the translocated segment 15q22 and the normal chromosome 15. N 5 Normal chromosome; D 5 Derivative chromosome.

of (1q) was detected along with instability that was identical to that seen in ICF syndrome (variable immunodeficiency, centromere instability, and facial anomalies). The authors suggested that hypomethylation could be behind the mechanism of chromosome instability [31]. If JT is the result of genome instability, its occurrence might be more frequent than observed but less detectable because of loss during cell division. In the present case, the (3;6) translocation was not observed in every study (see Table 1). Either the translocation (3;6) was lost during cell division, or remained as undivided cells. The (3;9) translocation was more stable since more cells of (3;9) were identified (Table 1). The literature on acquired JT consists of cases with a poor prognosis. This prognosis was supported in the present case, which provided evidence of resistant leukemia with resistance to initial chemotherapy, early relapse after unrelated donor transplant, and then resistance to further chemotherapy and conventional retinoic acid. Fortunately, our patient entered a cytogenetic and molecular remission induction with liposomal retinoic acid and arsenic trioxide. REFERENCES 1. Lejeune J, Maunoury C, Prieur M, Van den Akker J (1979): Translocation sauteuse (5p;15q), (8q;15q), (12q;15q). Ann Genet 22:210–213.

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