Chronic myeloid leukemia with a rare variant Philadelphia translocation

Cancer Genetics and Cytogenetics 129 (2001) 76–79

Short communication

Chronic myeloid leukemia with a rare variant Philadelphia translocation: t(9;10;22)(q34;q22;q11) W. Emberger,a,* A. Behmel,a M. Tschernigg,a H.L. Seewann,b E. Petek,a P.M. Kroisel,a K. Wagnera a

Institute of Medical Biology and Human Genetics, University of Graz, Harrochgasse 21⁄8, A-8010 Graz, Austria b Department of Hematology Landeskrankenhaus Fürstenfeld, Krankenhouspasse 1, 8280 Fürstenfeld, Austria Received 14 December 2000; accepted 12 January 2001

Abstract

We report a 59-year-old, male, chronic myeloid leukemia patient with a rare variant Philadelphia (Ph) translocation t(9;10;22)(q34;q22;q11). Fluorescence in situ hybridization with whole chromosome paints was used to confirm the cytogenetic findings. With a BCR/ABL-specific probe, the known rearrangement on the derivative chromosome 22 was found. The prognostic implications as well as the relevance of the additional breakpoint region 10q22 are discussed. © 2001 Elsevier Science Inc. All rights reserved.

1. Introduction

2. Case report

In 1960, Nowell and Hungerford [1] described the presence of a small chromosome in the bone marrow cells of a patient with chronic myeloid leukemia (CML), which is now known as the Philadelphia (Ph) chromosome, the derivative chromosome 22 of the Ph translocation. By a more detailed cytogenetic investigation, a karyotype of t(9;22)(q34; q11) with breakpoints in the ABL gene and breakpoint cluster region (BCR) could be demonstrated [2]. This aberration was shown to be present in 90–95% of patients with CML [3]. The ABL proto-oncogene is translocated in inverted 5 to 3 position to the BCR [4]. Leukemogenesis is thought to result from the expression of a BCR/ABL chimeric transcript with tyrosinkinase activity [5]. Variant Ph translocations can be found in 5–10% of CML cases. They are divided into a simple form (involving 22q11 and one additional breakpoint) and a complex form (involving 22q11, 9q34, and at least one additional breakpoint) [6]. At the molecular level, the involvement of the ABL region in simple variant Ph translocations is frequently detected [7]. We present a detailed characterization, including molecular cytogenetic investigations of a variant Ph translocation involving chromosome 10, and will focus on the rare but recurrently described breakpoint region 10q22.

In July 1995, a 54-year-old male patient was admitted to the Department of Hematology for evaluation of leukocytosis. Physical examination revealed an enlarged liver at 3 cm below the costal margin; the spleen was palpable at the costal margin. The following hematologic parameters were found: hemoglobin 13.6g/dl; platelets 175  109/l and white blood cells 43.6  109/l with 40% neutrophils, 13% lymphocytes, 2% monocytes, 3% eosinophils, 3% basophils, 18% promyelocytes, 15% myelocytes, and 6% metamyelocytes. Laboratory parameters showed elevated liver enzymes (-glutamyltransferase 284mU/ml, aspartate aminotransferase 61mU/ml, and alanine aminotransferase at 72mU/ml), presumably due to alcohol abuse. Bone marrow was hypercellular with a dense population of myeloid cells. According to these findings, the diagnosis of CML was established and a cytogenetic evaluation was performed. Therapy with cytarabine and interferon  was administered and resulted in normalization of the peripheral blood values within two months. Because of leukopenia, cytarabine was discontinued several times and finally stopped in January 1998. Interferon therapy was continued and hydroxide carbamide was added from May to October 1999. The disease has not shown any significant clinical or cytogenetic progression within the past five years. 3. Cytogenetic and molecular cytogenetic studies

* Corresponding author. Tel.: 43-316-380-4120; fax: 43-316-3809605. Email address: [email protected] (W. Emberger).

G-banded chromosome spreads from unstimulated bone marrow cultures were investigated according to standard procedures and revealed the following karyotype:

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W. Emberger et al. / Cancer Genetics and Cytogenetics 129 (2001) 76–79

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46,XY,t(9;10;22)(q34;q22;q11)[16]/46,XY[9]. The results of cytogenetic analyses are shown in Table 1. Commercially available, differentially labeled fluorescence in situ hybridization (FISH) probes (BCR/ABL [ES]; Vysis, Stuttgart, Germany) were used to detect the rearranged BCR/ABL gene, and whole chromosome painting probes (WCP) were used to detect for chromosomes 10 and 22. The BCR/ABL probes were hybridized to interphase nuclei as well as to chromosome spreads. We found a clear, yellow, BCR/ABL fusion signal in interphase nuclei which could be refined to the smaller chromosome 22 on metaphase spreads, indicating that the breakpoint was located within the major breakpoint cluster region (Fig. 1a). The normal chromosome 9 and the derivative chromosome 9 showed the ABL signal and the normal chromosome 22 the BCR signal. The WCP for chromosome 10 (Fig. 1b) showed signals on normal and derivative chromosome 10 as well as on the derivative chromosome 9. The WCP of chromosome 22 (Fig. 1c) showed an additional signal on the derivative chromosome 10. 4. Discussion In the present observation, FISH analysis demonstrated the presence of a BCR/ABL rearrangement in a variant Ph translocation. Sessarego et al. [8] suggested that variant Ph translocations may result from a two-step process with primary formation of the classical rearrangement and a second aberration event, in contrast to a one-step complex chromosomal rearrangement based on simultaneous chromosomal break events, assumed by Fitzgerald et al. [9]. Our results showed no evidence for a second break event of one of the involved chromosomes, but a two-step process can not be ruled out completely. Table 1 Results of cytogenetic studies Date of probe sampling

Type of sample

Karyotype

8/25/1995

Bone marrow

46,XY,t(9;10;22)(q34;q22; q11)[16]/46,XY[9] 46,XY,t(9;10;22)(q34;q22; q11)[9]/46,XY[1] 46,XY,t(9;10;22)(q34;q22; q11)[3]/46,XY[17] 46,XY[10] 46,XY,t(9;10;22)(q34;q22; q11)[7]/46,XY[13] 46,XY[10] 46,XY,t(9;10;22)(q34;q22; q11)[12]/46,XY[2] 46,XY,t(9;10;22)(q34;q22; q11)[2]/46,XY[9] 46,XY,t(9;10;22)(q34;q22; q11)[13]/46,XY[5] 46,XY[20] 4446,XY,10[3], t(9;10;22)(q34;q22; q11)[cp49]/46,XY[9] 46,XY[10]

Peripheral blood 4/29/1996

Bone marrow

1/14/1997

Peripheral blood Bone marrow

3/3/1998

Peripheral blood Bone marrow Peripheral blood

9/10/1998

Bone marrow

5/9/2000

Peripheral blood Bone marrow

Bone marrow

Fig. 1. (a) BCR/ABL probes. ABL signals indicated by arrowheads, normal and derivative chromosome 9 in metaphase spreads; BCR signals indicated by arrow, chromosome 22 in metaphase spreads; BCR/ABL fusion signal indicated by open arrow, derivative chromosome 22 in metaphase spreads. (b) WCP 10. Signals on chromosome 10 (open arrow), on derivative chromosome 10 (arrowhead) and on derivative chromosome 9 (arrow). (c) WCP 22. Signals on chromosome 22 (arrowhead), derivative chromosome 22 (open arrow), and derivative chromosome 10 (arrow).

Variant Philadelphia translocations involving chromosome 10 are rare and only 22 cases have been described. Leukemogenesis is thought to result from the BCR/ABL fusion. No major differences between classical and variant Ph translocations have been described relating to prognosis or duration of the chronic phase. This leads to the theory that genes located on chromosomes other than 9 and 22 are not involved in the development of CML. These are wellknown facts, but no explanation for the rare but recurrent involvement of chromosomal subband 10q22 in variant Ph translocations can be given. A fact of interest is that the ma-

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[8]

[9]

[10]

[11]

[12]

[13]

[14] Fig. 2. Chromosome 10 breakpoints in variant Ph-translocations according to Mitelman et al. [11] and present case. [15]

jority of chromosome 10 breakpoints of variant Ph translocations described so far cluster to chromosomal subbands 10q22 and 10q26 (Fig. 2). These chromosomal regions deserve further attention. Breakpoints at 10q22 can be found not only in variant Ph translocations but also, even more frequently in other hemoblastoses, as summarized in Table 2. Ariyasu et al. [10] established and characterized biphenotypic acute leukemia cell lines with a variant Ph translocation, t(9;10;22)(q34;q22;q11), and described the involvement of 10q22 in variant Ph translocations in acute lymphoblastic leukemia (ALL). Further investigations, for example, positional cloning of the 10q breakpoint, could contribute to a better understanding of the role of this chromosomal region in hemoblastoses.

[16] [17]

[18]

[19]

[20]

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Table 2 Breakpoint 10q22 in hemoblastoses based on Mitelman et al. [11] Reference

Morphology

Karyotype

Raimondi et al. [12] O’Malley et al. [13]

ALL ALL

Martineau et al. [14]

ALL

Kennedy et al. [15] Anglani et al. [16] Willman et al. [17]

ALL AML AML

Wayne et al. [18] Seyger et al. [19] Schoch et al. [20]

AML AML with minimal differentiation APL

Petkovic et al. [21] Perot et al. [22] Pagano et al. [23] Oshimura et al. [24]

AMbL APL AMbL without differentiation AML

Maseki et al. [25] Marosi et al. [26] Kaneko et al. [27]

AMbL with differentiation APL AMybL with maturation AMyMcL

47,XX,t(10;12)(q22;p12),21 46,XX,ins(11;4)/46,idem,del(5)(q15q33)/46, idem,del(5)/47,idem,8/46,idem,t(9;10) (p13;q22) or t(9;10)(p22;q24) 46,XY,del(6)(q21q27),t(10;19)(q22;q13), add(12)(p12),I(21)(q10),idic(21)(p11) 46,XX,del(9)(p?),t(10;14)(q22;q11) ??,X?,t(1;10)(q21;q22) 44,XX,del(5)(q11q33),del(7)(q11),8, der(10)t(10;11(q22;q13)add(11)(q13), add(13)(q3?2),16)/44,idem,del(6) (q?15q?23) 46,XY,t(7;10(q34;q22),t(9;22) 47,XX,der(10)t(1;10)(q25;q22),t(12;17)(q13;q21) 46,XX,t(15;17)(q22;q21)/45,idem,del(6)(p12), t(9;10)(q34;q22),del(13)(q12q14),16 46,XX,inv(5)(q11q21),t(10;11;19) (q22;q25;q13) 45,XX,t(9;10)(p23;q22),21,22,mar 47,XX,t(7;10;11)(q22;q22;q21),t(7;10)(p21;p11),8 44,XX,der(9)t(9;10)(q34;q22) or t(9;10)(q22;q11),10,del(14)(q22),17 46,XY,t(9;10)(p13;q22),inv(16)(p13q22) 46,XY,t(1;10)(p22;q22),t(15;17)(q22;q21),del(17)(p12) 46,XX,t(4;10)(q31;q22),t(6;9)(p23;q34) 40–45,XY,t(1;7;17)(p34;q36;q11),2,5,10, i(11)(q10)x2,add(11)(q23),13,add(14) (q32),del(15)(q24),17,der(19)t(10;19) (q22;q13),20,21,22,mar 46,XY,del(3)(?p21),t(10;11)(?q22;?q23) 43,XY,t(6;10)(p25;q22),7,del(9)(q12),del(10) (p13),inv(11)(p15q13),add(16)(p1?1),17,18 der(19)t(17;19)(q13;q21),add(20)(q13) 45,XX,del(5)(q14q34),7,8,der(10)t(10;17) (q22;p1?3),add(12)(p11),17, 20,der(20t(7;20)(p13;p1?3),1–3mar 46,XY,der(3)t(3;8)(q22;q11),der(5)t(5;10) (q33;q22),7,del(7)(q21),der(9)t(4;9) (q11;p24),der(10)t(10;13)(q22;q21),t(12), del(19)(p13),del(22)(q11) 46,XX,t(2;10)(p23;q22),t(4;11)(q21;q23), t(4;16)(q21;p13),t(14;18)(q32;q21)/46, idem,X,8 46,XY,t(10;14)(q22;q32),add(15)(p11), 16,mar 46,XY,3,t(10;19)(q22;p13)

Billström et al. [28]

Grimwade et al. [29] Le Beau et al. [30]

AMybL with maturation AML

Le Beau et al. [30]

AML

Mark et al. [31]

Non-Hodgkin lymphoma

Dyer et al. [32]

Non-Hodgkin lymphoma

Hossfeld & Schmidt [33] Shinohara et al. [34]

Hodgkin disease,lymphocyte depletion CLL

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; AmbL, acute monoblastic leukemia; AMybL, acute myeloblastic leukemia; AmyMcL, acute myelomonocytic leukemia; CLL, chronic lymphocytic leukemia.