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Coexistence of Recurrent Chromosomal Abnormalities and the Philadelphia Chromosome in Acute and Chronic Myeloid Leukemias

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Coexistence of Recurrent Chromosomal Abnormalities and the Philadelphia Chromosome in Acute and Chronic Myeloid Leukemias Gong et al. Molecular Cytogenetics (2020) 13:34 https://doi.org/10.1186/s13039-020-00501-6 SHORT REPORT Open Access Coexistence of recurrent chromosomal abnormalities and the Philadelphia chromosome in acute and chronic myeloid leukemias: report of five cases and review of literature Jin-Ying Gong1† , Zhen-Hao Zhang2† , Wei Zhang1, Hui-Jun Wang1, Xiao-Fang Feng1, Ji Zhou1 and Guo-Qing Zhu1* Abstract Progression of chronic myelogenous leukemia (CML) is frequently accompanied by cytogenetic evolution. Additional genetic abnormalities are seen in 10–20% of CML cases at the time of diagnosis, and in 60–80% of cases of advanced disease. Unbalanced chromosomal changes such as an extra copy of the Philadelphia chromosome (Ph), trisomy 8, and i(17)(q10) are common. Balanced chromosomal translocations, such as t(3;3), t(8;21), t(15;17), and inv(16) are typically found in acute myeloid leukemia, but rarely occur in CML. Translocations involving 11q23, t(8; 21), and inv(16) are relatively common genetic abnormalities in acute leukemia, but are extremely rare in CML. In the literature to date, there are at least 76 Ph+ cases with t(3;21), 47 Ph+ cases with inv(16), 16 Ph+ cases with t(8; 21), and 9 Ph+ cases with t(9;11). But most of what has been published is now over 30 years old, without the benefit of modern immunophenotyping to confirm diagnosis, and before the introduction of treatment regimes such as TKI. In this study, we explored the rare concomitant occurrence of coexistence current chromosomal translocation and t(9;22) in CML or acute myeloid leukemia (AML). Keywords: Chronic myelogenous leukemia, Acute myeloid leukemia, Balanced chromosomal abnormalities, Clonal evolution, t(9;22) Introduction [1–3]. Although cytogenetic evidence of clonal evolution The prognostic significance of clonal evolution in CML is in CML is common as the disease progresses to acceler- variable and depends on many factors, including the type ated or blast phase, its impact is dependent on the specific of cytogenetic changes, the time and phase of emergence chromosomal anomalies [4]. The coexistence of t(9; of clonal evolution, and other chromosomal abnormalities 22)(q34;q11.2) and recurrent chromosomal abnormalities is extremely uncommon, especially t(9;11) and t(3;21). * Correspondence: [email protected] Few such cases have been reported. To date, coexistence †Jin-Ying Gong and Zhen-Hao Zhang contributed equally to this work. 1State Key Laboratory of Experimental Hematology, National Clinical Research of t(9;11) and t(9;22) has not been reported in China. Center for Blood Diseases, Institute of Hematology and Blood Diseases Here, we have characterized 5 cases of hematologic malig- Hospital, Chinese Academy of Medical Sciences and Peking Union Medical nancy exhibiting coexistence of t(9;22) and recurrent College, 288 Nanjing Road, Heping District, Tianjin 300020, People’s Republic of China chromosomal abnormalities, including two cases of t(9;11) Full list of author information is available at the end of the article and one case each of t(3;21), t(8;21) and inv(16). © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gong et al. Molecular Cytogenetics (2020) 13:34 Page 2 of 9 Materials and methods FISH of metaphase cells Patients FISH analyses of metaphase cells were performed to con- A retrospective study was conducted on 1382 patients firm Ph translocation and the presence of t(9;11), t(3;21), with hematologic malignancies displaying t(9;22) translo- t(5;7) or inv(16). FISH analysis was performed on a R- cations who were treated at the outpatient department banded slide for metaphase mapping to detect BCR/ABL1 or inpatient ward of the Blood Diseases Hospital (Insti- fusion gene and MLL/AF9, EVI1, CBFβ,andEGR1/ tute of Hematology), Chinese Academy of Medical D5S721. After karyotype analysis, a well-dispersed meta- Sciences between January 2016 and December 2018. phase mitosis figure with clear band and chromosomal ab- These patients included 834 males and 548 females, normalities was identified, photographs were taken, and giving a male-to-female ratio of 3:2. Five patients coordinates were recorded. Metaphase FISH was per- (0.36%) had additional rare recurrent genetic abnormal- formed on the same mitotic figure twice. Metaphase FISH ities: 2 patients had t(9;11), 1 patient had t(3;21), 1 was performed using a BCR/ABL1 and MLL/AF9 dual- patient had t(8;21), and 1 patient had inv(16). The fusion probe; an EVI1 and CBFβ dual-color separation clinical and laboratory data from these 5 patients are probe, and an EGR1/D5S721 dual-color deletion probe. described in detail. This study (registration no. BCR/ABL1, CBFβ, and EGR1/D5S721 probes were from NI2020002-EC-1) was approved by the institutional re- Abbott Diagnostics (Vysis, IL); MLL/AF9 and EVI1 probes view board of the Institute of Hematology and Blood were from Cytocell (Cambridge, UK). Sample slides were Diseases Hospital Chinese Academy of Medical Sciences deparaffinized in xylene for 10 min, destained in methanol and informed consent was obtained from all subjects. for 10 min, fixed in fresh fixative solution for 10 min, dehydrated through a graded series of ethanol solutions, and air-dried overnight. Probes were denatured and hy- Cytogenetic analysis bridized according to the manufacturer’s instructions. Chromosomal analyses were performed by examining short- Since samples had been treated with a hot salt solution, term cultures of bone marrow specimens according to the denaturation temperature was increased to 75–78 °C, standard conventional cytogenetic protocols. Fresh bone and the denaturation time was extended to 5 min. Samples marrow was collected from each patient and cultured for were rapidly washed, 10 μl of DAPI/antifade reagent was 24 h (in RPMI 1640 medium, 20% calf serum) without added to each sample, and slides were covered. Analysis addition of any growth factors. A methanol–glacial acetic was performed using an Isis system (Metasystems, acid fixation method was used for obtaining metaphase cells, Germany). and R-banding was performed. Analysis was performed using an Ikaros automated scanning system (Metasystems, Real-time quantitative RT-PCR assay Germany). At least 20 cells in metaphase were analyzed in A real-time quantitative reverse transcription–polymerase each case. Karyotype descriptions are based on the Inter- chain reaction (RT-PCR) assay was performed for the detec- national System for Human Cytogenomic Nomenclature tion of BCR/ABL1,MLL/AF9,AML/ETO,CBFβ/MYH11 and (ISCN 2016). AML1-MDS/EVI1 fusion gene transcripts. RNA was ex- tracted from bone marrow samples using Trizol reagent (Gibco-BRL, Gaithersburg, MD) according to the manufac- Fluorescent in situ hybridization analysis turer’s instructions. Reverse transcription was performed on FISH of interphase cells 1 μg of total RNA using random hexamers and superscript Fluorescence in situ hybridization (FISH) was performed II reverse transcriptase (Gibco-BRL) as described previously. on interphase nuclei of samples. FISH analyses were per- The resulting complementary DNA was subjected to PCR formed to confirm Ph translocation and the presence of to amplify fusion transcripts in an ABI 7500 real-time quan- t(8;21). Dual color-dual fusion labeled LSI AML1/ETO titative PCR instrument. Reaction systems using primers and LSI BCR/ABL1 probes (Abbott Diagnostics, IL, USA), and conditions were as described previously [5, 6]. These re- designed for their respective purposes. The slides were sults were then used to calculate the copy number of each pretreated with 2× sodium saline citrate, pH 7.0, for 30 target gene and its internal reference gene ABL1 based on a min at 37 °C, followed dehydrated in 70, 85, and 100% standard curve. Target gene mRNA level (%) = (copy num- ethanol solutions for 2 min. Probes were denatured and ber of target gene / copy number of ABL1) × 100%. hybridized according to the manufacturer’s instructions. Samples were rapidly washed, 10 μl of DAPI/antifade re- Flow cytometric immunophenotyping agent (Abbott Diagnostics, IL, USA) was added to each Eight-color multiparametric flow cytometry (MFC) was sample, and slides were covered. Analysis was performed performed on peripheral specimens or bone marrow using an Isis system (Metasystems, Germany). Five hun- specimens using BD FACSCanto II instruments (BD dred interphase cells were analyzed per specimen. Biosciences) according to the manufacturer’s Gong et al. Molecular Cytogenetics (2020) 13:34 Page 3 of 9 instructions. Incubation of cells with monoclonal anti- the t(9;11)(p22;q23) abnormality. These 2 patients were bodies at 4 °C was followed by RBC lysis with NH4Cl for confirmed as having both t(9;22) and t(9;11) in the same 10 min and washing with phosphate-buffered saline solution.
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