Variant Philadelphia translocations with different breakpoints in six chronic myeloid leukemia patients / Alti kronik miyeloid losemi olgusunda farkli kirik noktali varyant Philadelphia translokasyonlari.
Subject: Chronic myeloid leukemia (Development and progression)
Cancer (Care and treatment)
Chromosomes
Fluorescence
Authors: Kuru, Dilhan
Arguden, Yelda Tarkan
Ar, Muhlis Cem
Cirakoglu, Ayse
Ongoren, Seniz
Yilmaz, Sukriye
Eskazan, Ahmet Emre
Deviren, Ayhan
Soysal, Teoman
Hacihanefioglu, Seniha
Ulku, Birsen
Pub Date: 09/01/2011
Publication: Name: Turkish Journal of Hematology Publisher: Aves Yayincilik Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2011 Aves Yayincilik ISSN: 1300-7777
Issue: Date: Sept, 2011 Source Volume: 28 Source Issue: 3
Product: Product Code: 8000432 Cancer Therapy NAICS Code: 621 Ambulatory Health Care Services
Accession Number: 305562368
Full Text: Abstract

Objective: The Philadelphia (Ph) chromosome, consisting of the t(9;22)(q34;q11) translocation, is observed in--90% of patients with chronic myeloid leukemia (CML). Variant Ph translocations are observed in 5%-10% of CML patients. In variant translocations 3 and possibly more chromosomes are involved. Herein we report 6 CML patients with variant Ph translocations.

Materials and Methods: Bone marrow samples were examined using conventional cytogenetic meth ods. Fluorescence in situ hybridization (FISH) with whole-chromosome paints and BCR-ABL 1D probes were used to confirm and/or complement the findings, and identify rearrangements beyond the resolution of conventional cytogenetic methods.

Results: Variant Ph translocations in the 6 patients were as follows: t(7;22)(p22;q11), t(9;22;15) (q34;q11;q22), t(15;22)(p11;q11), t(1;9;22;3)(q24;q34;q11;q21), t(12;22)(p13;q11), and t(4;8;9;22) (q11;q13;q34;q11).

Conclusion: Among the patients, 3 had simple and 3 had complex variant Ph translocations. Two of the presented cases had variant Ph chromosomes not previously described, 1 of which had a new complex Ph translocation involving chromosomes 1, 3, 9, 22, and t(1;9;22;3)(q24;q34;q11;q21) apart from a clone with a classical Ph, and the other case had variant Ph translocation with chromosomes 4, 8, 9, and 22, and t(4;8;9;22)(q11;q13;q34;q11) full complex translocation. Number of studies reported that some patients with variant Ph translocation were poor responders to imatinib. All of our patients with variant Ph translocations had suboptimal responses to imatinib, denoting a poor prognosis also. ariant Ph translocations may be important as they are associated with prognosis and therapy for CML patients. (Turk J Hematol 2011; 28: 186-92)

Key words: Chronic myeloid leukemia (CML), variant Ph chromosome, cytogenetics, fluorescence in situ hybridization (FISH)

Received: June 25, 2010

Accepted: August 19, 2010

Ozet

Amac: t(9;22)(q34;q11) sonucu olusan Philadelphia (Ph) kromozomu, kronik miyeloid losemi (KML) olgularinin %90' dan fazlasinda gozlenir. KML hastalarinin %5-10 unda varyant Ph translokasyonlari bulunur. Varyant translokasyonlar uc ve daha fazla kromozom icerebilmektedir. Bu calismada varyant Ph translokasyonlu 6 KML olgusu sunulmaktadir.

Yontemler ve Gerecler: Kemik iligi ornekleri konvansiyonel sitogenetik kullanilarak incelendi; BCR-ABL 1D problarinin kullamldigi Floresan In Situ Hibridizasyon (FISH) yontemi bulgularin dogrulan-masi ve konvansiyonel sitogenetik yontemlerinin tespit etmekte yetersiz kaldigi yeniden duzenlemele-rin tanimlanmasi amaciyla uygulandi.

Bulgular: calismada yer alan 6 hastanin varyant Ph translokasyonlari: t(7;22)(p22;q11), t(9;22;15) (q34;q11;q22), t(15;22)(p11;q11), t(1;9;22;3)(q24;q34;q11;q21), t(12;22)(p13;q11) ve t(4;8;9;22) (q11;q13;q34;q11) dir.

Sonuc: Uc olguda bash, 3 olguda ise karmasik (kompleks) varyant Ph translokasyonlari saptaims bulunuyoruz. Olgularimizin ikisi daha once bildirilmeyen varyant Ph kromozomlari tasiyorlardi. Bu olgulardan biri klasik Ph'li bir klonun yanisira 1, 9, 22 ve 3 numarahli kromozomlari iceren t(1;9;22;3) (q24;q34;q11;q21) formullu yeni bir kompleks Ph translokasyonuna; digeri ise 4, 8, 9 ve 22 numarah kromozomlari iceren t(4;8;9,22)(q11;q13;q34;q11) kompleks translokasyonlu varyant Ph'ya sahipti-ler. Varyant Ph'li 6 olgunun tumu kotu prognoza isaret eden yetersiz imatinib cevabi gosterdiler. (Turk J Hematol 2011; 28: 186-92)

Anahtar kelimeler: Kronik myeloid losemi (KML), varyant Philadelphia kromozomu, sitogenetik, floresan in situ hibridizasyon (FISH)

Gelis tarihi: 25 Haziran 2010

Kabul tarihi: 19 Agustos 2010

Introduction

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm arising from neoplastic transformation of a pluripotent stem cell. The Philadelphia (Ph) chromosome, which is the result of t(9;22)(q34;q11), is observed in ~90% of CML patients. The translocation leads to fusion of the proto-oncogene Abelson (ABL) and a particular DNA sequence known as breakpoint cluster region (BCR), thereby giving rise to 2 new chimeric genes 5' ABL-3' BCR on the derivative chromosome 9 and 5' BCR-3' ABL on the derivative chromosome 22. Variant Ph translocations have been observed in 5%-10% of CML patients (1). These variant translocations may be simple or complex. Simple variant translocations occur when the deleted segment of 22q is translocated onto a chromosome other than chromosome 9. In complex translocations, 3 and possibly more chromosomes are involved (2), (3). In a few cases of variant Ph translocations the BCR-ABL fusion gene is located on chromosomal sites other than 22q11 (4).

More than 1 mechanism plays a role in the evolution of variant Ph translocation; it can originate secondary to simple Ph translocation or can arise simul-taneously in a 3-way rearrangement. Different mechanisms involved in the formation of a variant translocation may have different clinical implications: a 2-step evolution might resemble a clonal evolution, whereas variant translocations that evolve simultaneously in a 3-way rearrangement may be similar to simple Ph translocation (5). The clinical significance of variant t(9;22) translocations is not clear (4).

In the present study bone marrow samples from 6 CML patients were examined using conventional cytogenetic methods, FISH with whole-chromo-some paints, and BCR-ABL 1 D probes to confirm and/or complement the findings, and identify rear-angements beyond the resolution of conventional cytogenetic methods. Additionally, 2 of the CML patients had new complex translocations; 1 between chromosomes 1, 3, 9, 22, and other between 4, 8, 9, and 22. Possible correlations between chromosome breakpoints other than 9 and 22 in these Ph variant tranlocations, and recent updates for the map locations of consistent cancer breakpoints, fragile sites, and oncogenes are discussed.

Materials and Methods

Patients

The study included 6 clinically diagnosed CML patients that were referred for cytogenetic analysis and had variant Ph translocations. Clinical features of the patients are shown in Table 1.

Cytogenetic and FISH analysis

Bone marrow (BM) samples were used for cytogenetic and FISH analysis.

Cytogenetics

Cytogenetic analysis was performed on overnight and 24-h unstimulated BM cultures using standard procedures. The GTL (G-bands via trypsin using Leishman) banding technique (6) was applied to the slides, karyotypes were described according to the International System for Human Cytogenetic Nomenclature (2005) (7), and 15-20 metaphases were analyzed for each sample.

FISH analysis

Fresh slides were used for FISH analysis. Before hybridization the slides were pretreated with pepsin, followed by post-fixation and denaturation. FISH analysis was performed according to the manufacturer's protocols. BCR-ABL1 rearrangement was examined using a BCR-ABL1 D-FISH probe (BCR: 500 Kb in red; ABL1: 600 Kb in green; Oncor, Inc., Gaithersburg, MD, USA).

FISH analyses using whole chromosome paint (WCP) probes to characterize only complex variant translocations in patients 2, 4 and 6.: for patient 2 painting probes for chromosomes 15 and 22 were digoxigenin labeled (WCP 15 and WCP 22; Oncor, Gaithersburg, MD, USA); for patient 4 painting probes for chromosomes 1, 9, and 22 (WCP 1, 9, and 22; XCP-MetaSystems); for patient 6 painting probes for chromosomes 4, 8, 9, and 22 (WCP 4, 8, 9, and 22; XCP-MetaSystems and Cytocell). Fluorescence microscopy was performed with a Nikon E600 microscope with a tri-ple-pass filter and a cooled monochrome CCD camera, using MacProbe FISH analysis software and a CytoVision Ultra system (Applied Imaging, Pittsburgh, PA).

Results

Variant Ph translocations were identified in all 6 patients using G-banding analysis, and were confirmed via FISH analysis. G-banding and FISH results are shown in Table 2.

Cytogenetics

In all, 3 of the patients (1, 3, and 5) had simple variant Ph translocations and 3 (2, 4, and 6) had complex translocations. Among the complex variant Ph translocations, 3 chromosomes were involved in 1 patient (2) and 4 chromosomes were involved in 2 patients (4 and 6). Clonal evolution was observed only in patient 4; there were 2 clones 1 with a classical Ph and 1 with t(1;9;22,3) (q24;q34;q11;q21). The chromosomal breakpoints of the variant Ph translocations were 1 q24, 3q21, 4q11, 7p22, 8q13, 12p13,15p11, and 15q22. In patient 3 additional clonal chromosomal changes along with variant Ph translocation were observed [t(13,15) (p11;q13)]. Partial G-banding karyotypes are presented in Figure 1.

[FIGURE 1 OMITTED]

FISH analysis

In 5 patients (1, 3, 4, 5, and 6) dual-color FISH with the use of the BCR and ABL probes showed the BCR-ABL fusion gene on the Ph chromosome. In patient 2 BCR and ABL probes could not be used due to insufficient material. With the WCP probes involvement of chromosomes other than 9 and 22 in the complex variant translocations were confirmed in patients 2, 4, and 6. FISH images are shown in Figure 2.

[FIGURE 2 OMITTED]

Discussion

In the present study chromosomal breakpoints of the variant Ph translocations other than classical 9 and 22 breakpoints were 1q24, 3q21, 4q11, 7p22, 8q13, 12p13,15p11, and 15q22. All 8 breakpoints observed in the 6 patients are listed as variant Ph translocations in the Mitelman database (http://www.cgap.nci.nih.gov/Chromosomes/Mitelman; updated 23 February 2009) (8). Among the chromosomes that constituted variant Ph translocations in the presented patients, those that were previously described are shown in Table 3.

It was reported that breakpoints involved in variant Ph translocations are primarily located in light-staining bands (2). Apart from 1q24, the breakpoints observed in the present study were also in light-staining bands. Most of the breakpoints observed in the present study harbor genes known to be associ--ated with neoplasia. GPA33 in 1q24, DIRC2 and HSPBAP1 in 3q21, BTL in 4q11, ETV6 in 12p13, and PML in 15q22 genes are implicated in different leukemias and solid tumors, but the gene in 8q13 is unknown (20). Band 7p22 in patient 1 corresponded to the map location of common fragile sites (21).

Among the 6 presented patients, 3 had simple and 3 had complex variant Ph translocations. To the best of our knowledge only a few cases of variant Ph translocations involving > 3 chromosomes have been reported [1,5,9,11-19,22,231. In all, 2 of the presented patients (4 and 6) had 4-way rearrangement [t(1;9,22;3)(q24;q34;q11;q21) and t(4;8;9;22) (q11;q13;q34;q11)], including breakpoints that differed from those previously reported. CML studies reported 1q24 and 3q21 in simple and 3-way variant Ph translocations (8), (20). The literature does not contain any reports of 4-way complex translocations involving the chromosomal band 1 q24 in CML patients. Similarly, simple and complex variant Ph translocations involving chromosomal bands 4q11 and 8q13 have not yet been reported in CML patients. In CML patients 8q13 has been reported in translocations other than Ph and 4q 11 was reported in association with ANLL (8), (18), (20). Specific chromosomal abnormalities involving band 3q21 have been observed in all FAB subtypes of acute myeloid leukemia (AML), in myelodysplastic syndrome, occasionally in the blastic phase of chronic myeloid leukemia, and rarely in chronic phase CML.

In some older studies variant Ph translocations involving 3q21 were considered a marker of poor prognosis in CML, and were used to justify the necessity of increasing the dose of imatinib, as commonly administered in the accelerated phase (24). Patient 4 in the present study did not have a hematological or cytogenetic response to imatinib. Consequently, imatinib was replaced by dasatinib, which was administered for 1 year, but also did not result in a cytogenetic or hematological response. Excluding patient 3, all the presented patients with variant Ph translocations were poor responders to imatinib and were therefore treated with dasatinib.

The strongest evidence for serial stepwise rearrangements resulting in variant Ph translocation comes from the rare observation of patients with a standard Ph in 1 clone and a complex variant Ph in another clone, as in patient 4 in the present study, who had 1 clone with t(9;22)(q34;q11) and 1 clone with a complex variant Ph translocation t(1,9,22;3)(q24;q34;q11;q21). Cytogenetic evidence suggests that complex Ph translocation is derived from simple Ph translocation (17), (25).

The breakpoints of variant Ph translocations in CML patients may be important, as they are associated with carcinogenesis. Above all, monitorization of chromosomes and localization of precise breakpoints involved in the complex rearrangements in CML patients will improve our understanding of the genetic mechanisms that play a role in the progression of malignant disease. We trust that the present study's results will contribute to the scientific community's knowledge of CML cytogenetics. Written informed consent was obtained from all the patients.

Conflict of interest statement

The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.

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Dilhan Kuru (1), Yelda Tarkan Arguden (1), Muhlis Cem Ar (3), Ayse Cirakoglu (1), Seniz Ongoren (3), Sukriye Yilmaz (1), Ahmet Emre Eskazan (3), Ayhan Deviren (2), Teoman Soysal (3), Seniha Hacihanefloglu (2), Birsen Ulku (3)

(1) Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey

(2) Department of Medical Genetics, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey

(3) Department of Internal Medicine, Division of Hematology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey

Address for Correspondence: Dr. Dilhan Kuru, Department of Medical Biology, Cerrahpas Faculty of Medicine, Istanbul University, Istanbul, Turkey Phone: +90 212 414 30 34 E-mail: dilhank@istanbul.edu.tr

doi: 10.5152/tjh.2011.52
Table 1. Clinical features of the patients

Case                    1      2     3          4           5       6

Age/Sex               39/F   23/M  52/M          33/F     60/F   32/M

Reason for referral    CML    CML   CML           CML      CML    CML

Splenomegaly (cm         0     NA     0            15       0      25
below the costal
margin)

Hemoglobin level       9.7    NA   13.9           9,7      11     8,4
(g/dL)

Platelet count         360    NA    220           360     180     214
([mm.sup.3])

Leukocyte count       75.4    NA   67.7           160    69,7   123,7
([mm.sup.3])

Blasts in PB (%)         1    NA      0             1       0       3

Sokal score            Low    NA    Low  Intermediate     Low    High

Best cytogenetic       PCR    NA    CCR           NCR     NCR     NCR
response

Treatment              HU,    NA    HU,      HU, IFN,     HU,     HU,
                      IFN,         IFN,    ARA-C, IM,      GL   IM, D
                       IM          I M              D

NA; Not Available; F: Female; M: Mate; PB: Peripheral Blood;
HU: Hydroxyurea; INF: Interferon; ARA-C: Cytosine arabinoside;
JM: Imatinib mesylate; D: Dasatinib; PCR: Partial cytogenetic response;
CCR: Complete cytogenetic response; NCR: No cytogenetic response


Table 2. G-Banding and FISH results in the patients

Patient                                                   Karyotype

1                                            46,XX,t(7;22)(p22;q11)

2                                   46, XY, t(9;22;15)(q34;q11;q22)

3                      46, XY, t(13;15)(p11;q13), t(15;22)(p11;q11)

4          46,XX,t(9;22)(q34;q11)/46XX,t(1;9;22;3)(q24;q34;q11;q21)

5                                           46,XX,t(12;22)(p13;q11)

6                              46, XY, t(4;8;9;22)(q11;q13;q34;q11)

Patient              Probe            Hybridization
                                      pattern

1          BCR-ABL1 D-FISH            BCR-ABL (+)

2          WCP 15 and 22              confirmed

3          BCR-ABL1 D-FISH            BCR-ABL (+)

4          BCR-ABL1 D-FISH WCP 1, 9,  BCR-ABL (+),
           22                         confirmed

5          BCR-ABL1 D-FISH            BCR-ABL (+)

6          BCR-ABL1 D-FISH WCP 4, 8,  BCR-ABL (+),
           BCR-ABL                    confirmed
           9


Table 3. Chromosomes involved in variant Ph translocations in the
6 patients and previously reported breakpoints

Chromosomes    Type of translocations reported in the     Reference
seen in our                  literature
cases

4pl4, 14q32             t(4;14;9;22)(pl4;q32;q34;qll)    Aoun et al.
                                                            2004 [1]

6q25, 8q22               t(6;8;9;22)(q25;q22;q34;qll)    Acar et al.
                                                            1997 [9]

1p36                           t(l;9;22)(p36;q34;qll)

3p25                           t(3;9;22)(p25;q34;qll)  Yehuda et al.
                                                            1999 [5]

4pl4                           t(4;9;22)(pl4;q34;qll)

12q22                         t(9;22;12)(q34;qll;q22)

7q22                           t(7;9;22)(q22;q34;qll)    Zagariaa et
                                                        al. 2004 [4]

8ql2                           t(8;9;22)(ql2;q34;qll)

3q26                           t(3;9;22)(q26;q34;qll)

4pl4                           t(4;9;22)(pl4;q34;qll)   Morel et al.
                                                           2003 [10]

4pl6                           t(4;9;22)(pl6;q34;qll)

6p22, 12ql3             t(6,9;12;22)(p22;q34;ql3;qll)    Zagariaa et
                                                            al. 2006
                                                                [11]

lq36                                 t(l;22)(q36;qll)

4q31                           t(4;9;22)(q31;q34;qll)

7ql2                           t(7;9;22)(q31;q34;ql2)    Zang et al.
                                                           1993 [12]

12q24.1                     t(9;22;12)(q34;qll;q24.1)

3q26.2, 17q21         t(3;17;9;22)(q26.2;q21;q34;qll)

1p36                 der(l)t(l;9;22)(p36.1;q34;ql1.2)

1q42                         t(l;9;22)(q42;q34;qll.2)

7qll.2           der(9;22;7)ins(7;22)(q11.2;q 11q.12)   Reddy et al.
                           t(9;22;7)(q34;qll.2;qll.2)      2000 [13]

12P13                        t(9;22;12)(q34;11.2;P13)

15q15,             t(9;22;15;21)(q34;qll.2;ql5;qll.2)
21q11.2

1q25, 20ql3,    t(l;20;9;22;l)(q25;ql3;q34;qll.2;p35)
1p35

1p36                       t(l;9;22)(p36.1;q34;qll.2)

1q21                         t(l;9;22)(q21;q34;qll.2)

12P13                       t(9;22;12)(q34;qll.2;P13)   Costa et al.
                                                           2006 [14]

12ql3                       t(9;22;12)(q34;qll.2;ql3)

12pl3, 20ql2         t(9;22;20;12)(q34;qll.2;ql2;pl3)

1p36                           t(l;9;22)(p36;q34;qll)

3p11                           t(3;9;22)(pll;q34;qll)    Markovic et
                                                            al. 2000
                                                                [15]

3q12                           t(3;9;22)(ql2;q34;qll)

4q12                           t(4;9;22)(ql2;q34;qll)

1p36,11p15q23           t(l;ll;22)(p36.2;pl5ql3;ql2), Babicka et al.
                                                           2006 [16]

4q34                           t(4;9;22)(q34;q34;qll)

1p36                           t(l;9;22)(p36;q34;qll)

1q32                           t(l;9;22)(q32;q34;qll)

1q42                           t(l;9;22)(q42;q34;qll)

3p21                           t(3;9;22)(p21;q34;qll)

3q21                                 t(3;22)(q21;qll)

4pl4                           t(4;9;22)(P14;q34;qll)

4pl6                                 t(4;22)(pl6;qll)

4q31                           t(4;9;22)(q31;q34;qll)

7q11                           t(7;9;22)(qll;q34;qll)

7q32                           t(7,9,22)(q32;q34;qll)    Reid et al.
                                                           2003 [17]

12p12                               t(12;22)(pl2;qll)

12q13                          t(9;22;12)(q34;qn;ql3)

12ql4                         t(9;22;12)(q34;qll;ql4)

15q15                         t(9;22;15)(q34;qll;ql5)

15q15                               t(l5;22)(ql5;qll)

15q24                         t(9;22;15)(q34;qll;q24)

5q13,7q11                t(5;7;9;22)(ql3;qll;q34;qll)

6q24, 8q24               t(6;9;22;8)(q24;q34;qll;q24)

7q22,15q14              t(7;9;22;l5)(q22;q34;qll;ql4)

4q12                                 t(4;22)(ql2;qll)  Baxter et al.
                                                           2002 [18]

4q25                           t(4;9;22)(q25;q34;qll)   Sheth et al.
                                                           2005 [19]

Note. The same breakpoints with ours that involved in variant Ph
translocations in literature were marked by bold character
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