Constitutional T (8; 22)(Q24; Q11. 2) That Mimics the Variant Burkitt-Type Translocation in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia

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Constitutional t(8;22)(q24;q11.2) that mimics the variant Burkitt-type タイトル translocation in Philadelphia chromosome-positive chronic myeloid Title leukemia 著者 Kawamoto, Shinichiro / Yamamoto, Katsuya / Toyoda, Masanori / Author(s) Yakushijin, Kimikazu / Matsuoka, Hiroshi / Minami, Hironobu 掲載誌・巻号・ページ International Journal of Hematology,105(2):226-229 Citation 刊行日 2017-02 Issue date 資源タイプ Journal Article / 学術雑誌論文 Resource Type 版区分 author Resource Version 権利 © The Japanese Society of Hematology 2016. The original publication Rights is available at www.springerlink.com DOI 10.1007/s12185-016-2100-5 JaLCDOI URL http://www.lib.kobe-u.ac.jp/handle_kernel/90005660

PDF issue: 2021-10-07 Title: Constitutional t(8;22)(q24;q11.2) that mimics the variant Burkitt-type translocation in Philadelphia chromosome-positive chronic myeloid leukemia

Author names; Shinichiro Kawamoto, Katsuya Yamamoto, Masanori Toyoda, Kimikazu Yakushijin,

Hiroshi Matsuoka, Hironobu Minami

Running title: CML in CP with constitutional translocation t(8;22)

Type of manuscript:Case report

Department of Medical Oncology/Hematology, Kobe University Hospital, Kobe, Japan

Corresponding author: Shinichiro Kawamoto, M.D., PhD.,

Address: Chuoh-ku Kusunokicho 7-5-2, Kobe City 650-0017, Hyogo, Japan

TEL：+81-78-382-5111

FAX：+81-78-382-5821

E-mail: [email protected]

Text word count: 1408

Number of figures: 2

Abstract

Constitutional translocations that coincide with t(9;22)(q34;q11.2) might result in unnecessary treatments to chronic myeloid leukemia (CML) patients, because the diagnosis of CML with additional chromosomal abnormalities indicates an accelerated phase (AP) according to the standard criteria. A 47- year-old male had pain in the right foot due to gout. Peripheral blood examination showed leukocytosis with left shift. Bone marrow aspiration revealed myeloid hyperplasia with megakaryocytosis. RT-PCR revealed the major BCR-ABL fusion transcript and CML in the chronic phase was diagnosed followed by nilotinib treatment. Although WBC counts decreased immediately, G-banding analysis showed

46,XY,t(8;22)(q24;q11.2),t(9;22)(q34;q11.2)[20]. The t(8;22)(q24;q11.2) is known as a recurrent translocation in Burkitt’s lymphoma. The diagnosis was changed to CML in AP leading to B-lymphoid crisis. Unexpectedly, the karyotype was 46,XY,t(8;22)(q24;q11.2)[20] in hematological complete remission even after three months. Fluorescence in situ hybridization on metaphase spreads revealed the

MYC signal on the der(22)t(8;22), indicating that the 8q24 breakpoint was centromeric to MYC at

8q24.21. G-banding analysis of phytohemagglutinin stimulated peripheral blood T-lymphocytes also demonstrated 46,XY,t(8;22)(q24.1;q11.2). We conclude that the t(8;22) is constitutional in the patient. As the tumor suppressor gene TRC8/RNF139 is disrupted by constitutional t(8;22)(q24.13;q11.21) in dysgerminoma, there might be a possibility of its association with the onset of CML.

Key words: CML, Constitutional, non-Robertsonian translocation, t(8;22)

Introduction

Treatment for CML has changed dramatically after the emergence of tyrosine kinase inhibitors

(TKIs), and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is occasionally performed in

CML patients after disease progression to AP or blastic phase. Additional chromosomal aberrations including double Ph, +8, i(17q), and +19 are frequently observed in CML. These aberrations are categorized as major routes that reflect cytogenetic clonal evolution [1]. Wang et al. analyzed the aberrations in CML patients treated with TKIs and showed that better response was observed in a group with +8, -Y, and double Ph compared to in another group with i(17)(q10), -7/del(7q), and 3q26.2 rearrangements [2]. The former group with favorable aberrations showed equivalent responses to TKIs as those observed in CML patients without additional aberrations. Notably, in addition to these two groups,

47% of CML patients show other single aberrations. Mortality after allo-HSCT is much higher than that after treatment with TKIs. Furthermore, a portion of CML patients is able to discontinue TKIs treatment.

Thus, cases of Ph-positive CML with additional translocations at diagnosis require precise evaluation of cytogenetic analysis, especially in the TKIs era.

Reciprocal chromosomal translocations, such as t(8;21)(q22;q22) and t(15;17)(q22;q21) are well- known causes of leukemia and malignant lymphoma. These translocations are also reported to be rarely observed in CML. This is the first report of a Ph-positive CML patient with a constitutional t(8;22)(q24;q11.2) chromosomal translocation. As t(8;22)(q24;q11.2) is involved in the pathogenesis of

Burkitt’s lymphoma, the coincidence of these reciprocal translocations resulted in confusion regarding the disease status as being in B-lymphoid crisis at initial diagnosis.

Case report

A 47-year-old male with pain in the right foot due to gout and leukocytosis was referred to the

Kobe University hospital. The patient had no history of disease or intellectual deterioration. Peripheral blood examination showed leukocytosis with a left shift (WBC 20 × 109/L, myelocytes 4%, metamyelocytes 13%, stab cells 2%, segmented cells 58%, eosinophils 4%, basophils 4%, monocytes 7%, and lymphocytes 8%). The hemoglobin level was 15.4 g/dl and the platelet count was 353 × 109/L. CML was suspected owing to the increased number of basophils, and bone marrow aspiration was performed.

The bone marrow was hypercellular; the number of megakaryocytes were increased and the ratio of the cells were as follows: blasts 0.6%, promyelocytes 2.4%, myelocytes 11.4%, metamyelocytes 19.4%, stab cells 20.8%, segmented cells 27.4%, eosinophils 3.6%, basophils 1%, monocytes 0.4%, lymphocytes

1.8%, and plasma cells 0.4%. The major BCR-ABL transcript was detected at >626 copies/assay using the TMA method, and FISH analysis revealed the BCR-ABL fusion signal in 96% of the bone marrow cells (Figure 1A). From these results, CML in CP was diagnosed, and treatment was initiated immediately with a TKI, nilotinib, at a dosage of 800 mg daily. The WBC count decreased to 10.4 ×

109/L and 5.7 × 109/L at one week and two weeks after nilotinib administration, respectively. However, the BCR-ABL transcript was still detected at >626 copies/assay even after one month. Moreover, cytogenetic analysis revealed an abnormal karyotype, 46,XY,t(8;22)(q24;q11.2),t(9;22)(q34;q11.2)[20]

(Figure 2A). The clinical stage of the patient was reconsidered as AP leading to B-lymphoid crisis, because it is not merely an additional translocation but is a translocation that is observed in Burkitt’s lymphoma. The human leukocyte antigen was then analyzed for the preparation of allo-HSCT.

Surprisingly, cytogenetic analysis after treatment for three months only showed the chromosomal translocation t(8;22)(q24;q11.2): 46,XY,t(8;22)(q24;q11.2)[20] (Figure 2B), whereas the major BCR-

ABL transcript was barely detected under the measurable limit by real-time PCR. Moreover, metaphase

FISH revealed the MYC signal on der(22)t(8;22), indicating that the 8q24 breakpoint was centromeric to

MYC at 8q24.21. That is, t(8;22)(q24;q11.2) in the present case was different from that observed in

Burkitt’s lymphoma (Figure 1B). At this point, we speculated that t(8;22)(q24;q11.2) was a constitutional chromosomal translocation in this patient. Indeed, further chromosomal analysis using phytohemagglutinin (PHA)-stimulated peripheral blood T-lymphocytes also showed the identical chromosomal translocation as follows: 46,XY,t(8;22)(q24.1;q11.2)[20] (Figure 2C). Treatment with

4 nilotinib, without allo-HSCT, was continued afterwards and complete molecular response was maintained for at least 18 months after the initial diagnosis.

Discussion

Constitutional translocations that coincide with Ph-positive CML have been reported, most being

Robertsonian translocations, including t(13;14) )(q10;q10), t(14;15)(q10;q10), and t(15:22)(q10;q10) [3-

7]. On the other hand, non-Robertsonian translocations are rarely observed in Ph-positive CML [8].

The chromosomal translocation t(8;22)(q24;q11.2) in Burkitt’s lymphoma juxtaposes the MYC oncogene at 8q24 to the immunoglobulin light chain gene (IGL) at 22q11.2. The 8q24 breakpoints in t(8;22)(q24;q11.2) in Burkitt’s lymphoma are observed to be within 300 kb of the MYC 3′ UTR [9].

Because the t(8;22)(q24;q11.2) translocation detected in the present case was initially thought to be an additional translocation in CML, the patient was suspected to be in an accelerated phase leading to B- lymphoid crisis. However, FISH DNA probes designed against the flanking MYC 3′ UTR breakpoint on

8q24.2 loci did not detect a split signal. Moreover, the cytogenetic study of PHA-stimulated peripheral blood lymphocytes only showed the chromosomal translocation t(8;22)(q24.1;q11.2). These results indicate that t(8;22)(q24;q11.2) in the present case is a constitutional change and t(8;22)(q24;q11.2) was indeed found to persist after TKI treatment in our case, whereas t(9;22)(q34;q11.2) was lost.

Apart from hematological diseases, four recurrent constitutional non-Robertsonian translocations including t(11;22)(q23;q11), t(4;8)(p16;p23), t(8;22)(q24.13;q11.21), and t(9;22)(q34;q11.2), have been reported so far [10-14]. Among these, the presence of t(8;22) and t(9;22) definitely lead to confusion in diagnosis when the patients show abnormal findings in blood or physical examinations as in the present case, mainly because these translocations are frequently detected in hematological malignancies.

Constitutional t(8;22)(q24;q11.2) is occasionally found in females who are phenotypically normal carriers after the birth of intellectually deteriorated offspring. The wife of the male carrier experiences recurrent spontaneous abortions. Using PCR analysis of sperm DNA, Sheridan et al. demonstrated that t(8;22) occurs during gametogenesis in some healthy individuals [10]. In this case, we advised the patient and his daughter to undergo genetic counseling because carriers are at risk of bearing progeny with the supernumerary der(22)t(8;22) syndrome as a result of abnormally segregated der(22). This translocation is also observed in patients with abnormal hematological findings including leukocytosis and thrombocytosis [15].

Thus, the 22q11.2 locus is a hot spot for non-random chromosomal aberrations that result in deletion, supernumerary chromosomes, and interstitial duplications. The lesions on chromosome 22 that are

6 responsible for these rearrangements were identified in low copy repeats (LCRs). There are eight LCRs

(A to H) on chromosome 22 and these LCRs show 97%-98% sequence homology to each other [16,17].

Gotter et al. confirmed that the low copy repeat B on 22q11.2 is involved in t(8;22)(q24.13;q11.21) [18].

In contrast, the breakpoints on chromosome 8 in the t(8;22)(q24.13;q11.2) reciprocal constitutional translocation are identified in palindromic AT-rich repeats (PATRR) that are placed proximal to MYC

[19]. Gimelli et al. demonstrated that the tumor suppressor gene, TRC8/RNF139, on chromosome 8 is disrupted by t(8;22)(q24.13;q11.21) in a patient with dysgerminoma and suspected it as the cause for disease onset [20]. Moreover, the authors demonstrated that the interaction between TRC8/RNF139 and

VHL led to degradation of another tumor suppressor gene, CDKN1B/P27KIP [21]. Intriguingly, t(3;8)(p14;q24.1) observed in renal cell carcinoma, also involves this 8q breakpoint region [22, 23].

Therefore, it is possible that hematologic disorders with these constitutional translocations will result from the dysfunction of this tumor suppressor gene.

Conflict of interest

The authors declare that they have no conflict of interest.

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Figure 1 FISH analyses of bone marrow cells

(A) FISH with BCR-ABL probe on interphase nuclei at initial diagnosis. Arrows indicate 1) BCR

signal (green) on normal chromosome 22, 2) ABL1 signal (red) on normal chromosome 9, and

3) BCR-ABL1 fusion signal (yellow) on the der(22)t(9;22)(q34;q11.2).

(B) FISH with MYC probe on metaphase spreads at hematological complete remission.

Arrows indicate MYC signals (green and red) on 1) normal chromosome 8 and 2)

der(22)t(8;22)(q24;q11.2).

Figure 2 Chromosomal analyses

(A) G-banded karyotype of bone marrow cells at initial diagnosis: 46,XY,

t(8;22)(q24;q11.2),t(9;22)(q34;q11.2)[20].

(B) G-banded karyotype of bone marrow cells at remission: 46,XY,t(8;22)(q24;q11.2).

46,XY,t(8;22)(q24.1;q11.2).

Arrows indicate rearranged chromosomes.