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ZNF384 rearrangement in acute lymphocytic leukemia with renal involvement as the first manifestation is associated with a poor prognosis: a case report

ZNF384 rearrangement in acute lymphocytic leukemia with renal involvement as the first... Background: Novel fusion genes such as ZNF384, have been identified in B-cell precursor acute lymphoblastic leuke - mia (BCP-ALL) in recent years. Patients harboring ZNF384 rearrangements have a distinctive immunophenotype with weak CD10 and aberrant CD13 and/or CD33 expression. Thus, ZNF384-rearranged ALL is a unique subtype of BCP-ALL. However, research on the prognostic significance of ZNF384 rearrangements has been limited to date, especially in adolescents. Case presentation: We described a 17-year-old adolescent who was diagnosed with ALL and had renal involve- ment as the first manifestation, which was very rare in the existing studies. FISH analysis indicated a rearrangement of ZNF384 according to its probe. The patient had a typical characteristic immunophenotype of ZNF384 rearrange- ment, with CD10 negativity and CD13 and CD33 positivity. She had an unfavorable prognosis because she responded poorly to chemotherapy and developed a relapse shortly after reaching CR. Conclusion: The importance of ZNF384 rearrangements in terms of prognosis remains unclear. We reported an ado- lescent who was diagnosed with ZNF384-rearranged ALL with renal involvement. She underwent different therapies, but her prognosis remained poor. Since ZNF384 rearrangements may act as a prognostic predictor in children or adolescents, early detection based on its characteristic immunophenotype is of great necessity. Keywords: Acute lymphocytic leukemia, ZNF384, Gene rearrangement, Immunophenotype, Prognosis Background accounting for 0.3% of all new cancer cases [1]. ALL usu- Acute lymphocytic leukemia (ALL) is a malignant neo- ally occurs in children and young adults, with the peak plasm in which the differentiation of lymphoid cells is age ranging from 2 to 5 [2]. blocked at an early stage, and there is extensive infiltra - Gene rearrangements and fusions are common in tion in the bone marrow, peripheral blood, and other BCP-ALL, and they play an important role in determin- organs. Over 80% of ALL cases are B-cell precursor ing therapeutic targets and predicting prognosis. With acute lymphoblastic leukemia (BCP-ALL). In 2020, 6,150 the advancement of genome and transcriptome sequenc- new cases of ALL were diagnosed in the United States, ing, novel gene fusions, such as zinc-finger protein 384 (ZNF384) rearrangements have been found. The ZNF384 gene is located on chromosome 12p13. It encodes a zinc *Correspondence: cba8888@hotmail.com finger protein that functions as a transcription factor and Jinlong Ma and Jiaheng Guan contributed equally to this article regulates the expression of matrix metalloproteinases Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China [3]. In ZNF384-rearranged BCP-ALL, the breakpoints © The Author(s) 2022. 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://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ma et al. Molecular Cytogenetics (2022) 15:4 Page 2 of 6 of ZNF384 are typically located in exons 2 and 3, which CD10(+), CD3(−), CD4(−), CD8(−), CD38(+), contain the entire ZNF384 protein that may be respon- CD81(+), HLA-DR(+), CD19(+), CD22(+), CD20(+), sible for the characteristics of the immunophenotype [4, cMPO(−), cCD3(−), cCD79a(+), TDT(+), CD58(+), 5]. Therefore, the presence of ZNF384 rearrangements CD61(−), CD235a(−), and CD11c(−), and these find - should be a hallmark and the diagnostic criterion of a ings are compatible with BCP-ALL (Fig.  3). Next- separate subtype of BCP-ALL since patients harboring generation sequencing (NGS) showed STAG2 gene such rearrangements have a distinctive immunopheno- mutations in the bone marrow, and reverse transcrip- type. This immunophenotype includes weak CD10 and tion-polymerase chain reaction (RT–PCR) showed that aberrant CD13 and/or CD33 expression (6). common fusion genes for BCP-ALL, including TCF3- Recent data have shown that as many as 1% to 6% of PBX1, TCF3-HLF, ETV6-RUNX1 and BCR-ABL, were children and 5% to 15% of adults with BCP-ALL harbor negative. Other less common fusion genes for Ph-like ZNF384 rearrangements [7]. Although the incidence ALL were also negative. is not low, such rearrangements are difficult to detect Her medical history was unremarkable. On physical by conventional karyotype analysis, and there has been examination, the patient had an anemic appearance a lack of research on the prognosis of this rearrange- without ecchymosis. The initial laboratory evaluation ment for a long time. Furthermore, the liver, spleen, and revealed lymphocytosis (2.37 × 10 /l) and moderate lymph nodes are the most common sites of extramedul- anemia (Hb78 g/l, vitamin B12 164  pg/ml, folic acid lary involvement in ALL, with renal involvement being 3.00  ng/ml and serum ferritin 426.7 ug/l). She was relatively uncommon. The unique immunophenotype diagnosed with BCP-ALL with involvement of both of ZNF384 rearrangements helps to diagnose BCP-ALL kidneys. patients with rare sites of extramedullary involvement. After a cycle of the VCDLP regimen, the bone Herein, we report an adolescent case of ZNF384-rear- marrow was obviously hyperplastic and active, and ranged ALL with renal involvement as the first manifes - immature lymphocytes were occasionally observed. tation and poor prognosis. FCM showed the ratio of lymphoblasts was 42% with CD34(+), CD10(−), CD19(+), CD38(+), HLA-DR(+), CD64(−), CD13(+), CD20(−), and CD33(+). Since the Case presentation patient did not achieve remission, a cycle of FLAG sal- A 17-year-old female was admitted to our hospital in vage treatment was administered, and then the patient December 2019 because of increased urine foam and was assessed as complete remission (CR). No lympho- fatigue for 3 weeks. blasts were seen in the bone marrow. FCM showed Laboratory examinations showed protein (3+) and that the ratio of lymphoblasts was 0.8% with CD34(+), occult blood (2+) in urine. The blood urea nitrogen was CD10(−), CD19(+), CD38(+), HLA-DR(+), CD13(+) 5.39  mmol/l, the serum creatinine was 69  μmol/l, and and STAG2 gene mutations. The volume of both kid - the lymphocyte ratio was 62.01%. Kidney color Doppler neys returned to normal according to color Doppler ultrasound showed increased volume in both kidneys ultrasound. After the patient achieved CR, an intrath- as well as enhanced parenchymal echo. Then kidney ecal drug injection was performed for consolidation biopsy was performed, indicating lymphoblastic lym- therapy. Eight months after the continued complete phoma or leukemia with kidney involvement (Fig.  1A remission (CCR), the disease relapsed. A bone marrow and B). Immunohistochemistry showed TdT(+), smear revealed 55.2% lymphoblasts, and FCM showed CD99(+), CD3(−), CD20(part+), CD73(−), PAX5(+), ALL with partial expression of CD33. FISH showed and LCA(part+). Fluorescence in  situ hybridization ZNF384 rearrangement (39%) according to its probe (FISH) of the kidney biopsy sample indicated ZNF384 (Fig.  1F) and positivity for IgH rearrangement (37%). rearrangement (Fig. 1E). Then, bone marrow aspiration The leukemia fusion genes and mutation panels were and biopsy were performed, revealing the disappear- both negative. However, there was no remission in the ance of fat vacuoles and the appearance of immature bone marrow after she was treated with chidamide and lymphoid cells. However, conventional G-banding a dose-adjusted FLAG plus VP chemotherapeutic regi- cytogenetic analysis showed a normal bone marrow men, as well as a highly sensitive treatment, HAD. The karyotype (Fig.  2). A suspected diagnosis of ALL was percentage of lymphoblasts was 14.4% and ZNF384 made. There was extreme lymphocyte proliferation and rearrangement was positive (17.6%) according to FISH. the proportion of lymphoblasts was 50.8% (Fig.  1C and Currently, the patient has been admitted to the hospi- D). Flow cytometry (FCM) of bone marrow revealed tal and is receiving chemotherapy regularly. The details CD34(+), CD117(−), CD33(+), CD64(−), CD13(+), of the treatment process are summarized in Additional CD14(−), CD274(−), TSLPR(−), CD11b(−), IgM(+), file 1 . CD71(−), CD56(+), CD2(−), CD7(−), CD5(−), M a et al. Molecular Cytogenetics (2022) 15:4 Page 3 of 6 Fig. 1 Pathological results of kidney biopsy and bone marrow aspiration smear and results of FISH. A, B The result of kidney biopsy shows increased lymphocytes, indicating lymphoblastic lymphoma or leukemia with kidney involvement (A: HE staining; original magnification, ×400 and B: PAS staining; original magnification, ×400). C The result of Wright-Giemsa staining of the bone marrow smear sample is shown. Bone marrow hyperplasia is extremely active, with lymphoblasts accounting for 50.8% of cells before treatment ( Wright-Giemsa staining; original magnification, ×1000). D Lymphoblasts were negative for myeloperoxidase (red arrow), suggesting the possible diagnosis of acute lymphocytic leukemia (POX staining; original magnification, ×1000). E Fluorescence in situ hybridization (FISH) using a ZNF384 break-apart probe shows ZNF384 rearrangement in the kidney biopsy sample. Recognizable split signals can be seen in the scattered individual cells. The white arrows represent a single red signal and a single green signal (1R1G), which are split signals. The yellow arrow represents a single yellow signal (1Y ), which is a normal signal. 1R1G1Y is a positive signal model for ZNF384 rearrangement. F Describes the ZNF384 rearrangement (39%) in the bone marrow sample, indicating homology with the rearrangement of ZNF384 in the kidney biopsy sample. The two yellow arrows on the left represent two yellow signals, which are negative signals for ZNF384 rearrangement. The white arrows and the yellow arrows on the right are indicative of ZNF384 gene rearrangement (1R1G1Y ) Ma et al. Molecular Cytogenetics (2022) 15:4 Page 4 of 6 Fig. 2 Karyotype analysis of chromosomal G-banding. The G-banded karyotype of bone marrow cells showed a normal karyotype upon admission to our hospital effect of fusion proteins was the inhibition of B-cell dif - Discussion and conclusions ferentiation by introducing EP300, one of the fusion Patients harboring ZNF384 rearrangements are likely to genes, and ZNF384 into mouse pro-B cells, resulting in possess the characteristic immunophenotype of a dull or the stasis of cell differentiation [10, 11]. negative CD10 and aberrant expression of one or more The prognosis of ZNF384 rearrangements in children myeloid antigens. Thus, ZNF384-rearranged ALL is a or adolescents remains unclear. A retrospective study new subtype of leukemia that may be diagnosed as BCP- analyzed a total of 218 ZNF384-rearranged ALL cases, ALL [8]. CD10 was negative in our case, while CD13 with ages ranging from 1 to 25. The 5-year event-free sur - and CD33 were positive, which is consistent with previ- vival (EFS) rate was 85% (95% CI 78–90%), and the 5-year ous studies. The Tokyo Children’s Cancer Study Group overall survival (OS) rate was 91% (95% CI 85–95%) for (TCCSG) reported a similar outcome to ours. TCCSG all patients, suggesting a good outcome [12]. Mary Shago tested 91 samples from BCP-ALL patients, revealing also analyzed a cohort of 240 pediatric patients who were an incidence of a weak or negative expression of CD10, diagnosed with BCP-ALL. Seven of the 240 patients ranging from 0.39 to 67.34% (mean: 19.44 ± 18.23%), were identified to have ZNF384 rearrangements, with and 31.82% and 77.27% expression of CD13 and CD33, an average age of 5.1 years. The EFS ranges from 6 years respectively, in 22 patients with  ZNF384-related fusion 2  months to 9  years 2  months and all patients achieved genes [5]. remission with no relapse [13]. Although a few studies Unlike the mechanism by which subclonal genomic support a generally favorable prognosis in children or variation drives clonal evolution in the disease progres- young adults with ZNF384 rearrangements, others sug- sion of ALL [9], mutational variegation does not deter- gest a poor clinical outcome. A higher recurrence rate mine the immunophenotype for individual patients of over 2% was reported in some pediatric ZNF384 gene harboring ZNF384 rearrangements, and immunophe- fusion cases [5]. Nishimura reported two pediatric TCF3- notypic aberrancy arises from inherent lineage plasticity ZNF384-positive patients who developed disease relapse [8]. Moreover, fusion partners for ZNF384 are commonly more than 10  years after diagnosis [14]. Additionally, involved in BCP-ALL, which is responsible for leukemia CD10 negativity was found to be an independent adverse development. Preclinical studies found that the initial M a et al. Molecular Cytogenetics (2022) 15:4 Page 5 of 6 Fig. 3 The results of flow cytometry. The flow cytometry results indicated acute lymphocytic leukemia. A The proportion of primary cells was 68.45% according to the SSC/CD45 gating. B The CD22 fraction is shown as 22.8%. C CD19 was positive, with a proportion of 81.1%, and CD10 was positive, with a proportion of 20.9%. D CD34 was positive, with a proportion of 98.2%, and CD13 was positive, with a proportion of 55.8%. E CD20 was positive, with a proportion of 35.0%. F CD33 was positive, with a percentage of 69.8% prognostic factor in ALL because CD10-negative lymph- In conclusion, we report a BCP-ALL case with a oblastic leukemia cells had lower cycling capacities and ZNF384 rearrangement. The adolescent patient had were resistant to apoptosis [15, 16]. A cohort study in very rare renal involvement as the first manifestation. China investigating 111 pediatric patients with BCP-ALL However, she showed a very typical immunopheno- revealed that leukemic cells from patients with ZNF384 type of ZNF384-rearranged ALL with CD10 negativity fusions were more likely to be CD10-negative than those and CD13 and CD33 positivity. She responded poorly from other pediatric patients (18.8% vs. 2.9%, P = 0.02) to chemotherapy and developed a relapse shortly after (17). This finding may explain why children with ZNF384 achieving CR. Her bone marrow karyotype was normal, rearrangements have unfavorable outcomes. The ado - which may suggest that the ZNF384 rearrangement- lescent patient in our case had the distinct immunophe- related abnormal karyotype was under the detection notype of CD10 negativity, and she developed disease limit of conventional G-banding. This indicates that more relapse only eight months after she reached CR despite sensitive methods, such as FISH, should be used. Owing receiving consistent consolidation chemotherapy. She to the low detection rate and variety of treatment pro- also had poor responses to multiple chemotherapeutic tocols from institution to institution, the statistical sig- therapies, necessitating frequent adjustments to more nificance of clinical outcomes in children or adolescents effective and powerful regimens. Our report supple - with ZNF384 rearrangements has not been analyzed thus ments the unfavorable outcomes of adolescent patients far. However, it has been linked to an unfavorable prog- with ZNF384 rearrangements in the existing literature nosis in some small studies, but this still needs to be rep- and supports the view that ZNF384 rearrangements are licated on a larger scale to be confirmed. Furthermore, correlated with a poor prognosis. However, larger-scale ZNF384 break-apart probes are not commonly included multicenter studies are required to evaluate the exact in screening leukemia translocations, which could cause prognosis of ZNF384 rearrangements, especially in chil- a delay in diagnosis and treatment. Therefore, we suggest dren or adolescents. that when the rearrangement of ZNF384 is suspected Ma et al. Molecular Cytogenetics (2022) 15:4 Page 6 of 6 5. Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura based on its characteristic immunophenotype, it should K, et al. ZNF384-related fusion genes define a subgroup of childhood be tested and confirmed as soon as possible. B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica. 2017;102(1):118–29. 6. Gocho Y, Kiyokawa N, Ichikawa H, Nakabayashi K, Osumi T, Ishibashi T, Abbreviations et al. A novel recurrent EP300-ZNF384 gene fusion in B-cell precursor ALL: Acute lymphocytic leukemia; BCP-ALL: B-cell precursor acute lympho- acute lymphoblastic leukemia. Leukemia. 2015;29(12):2445–8. blastic leukemia; ZNF384: Zinc-finger protein 384; FISH: Fluorescence in situ 7. Lilljebjörn H, Fioretos T. New oncogenic subtypes in pediatric B-cell hybridization; FCM: Flow cytometry; NGS: Next generation sequencing; precursor acute lymphoblastic leukemia. Blood. 2017;130(12):1395–401. RT-PCR: Reverse transcription-polymerase chain reaction; CR: Complete remis- 8. Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, et al. The sion; CCR : Continued complete remission; TCCSG: The Tokyo Children’s Cancer genetic basis and cell of origin of mixed phenotype acute leukaemia. Study Group; EFS: Event-free survival; OS: Overall survival. Nature. 2018;562(7727):373–9. 9. Ma X, Edmonson M, Yergeau D, Muzny DM, Hampton OA, Rusch M, et al. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute Supplementary Information lymphoblastic leukaemia. Nat Commun. 2015;6:6604. The online version contains supplementary material available at https:// doi. 10. Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F, Kojima S, Ueno T, et al. Recur- org/ 10. 1186/ s13039- 022- 00583-4. rent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet. 2016;48(5):569–74. 11. Yaguchi A, Ishibashi T, Terada K, Ueno-Yokohata H, Saito Y, Fujimura J, et al. Additional file 1. EP300-ZNF384 fusion gene product up-regulates GATA3 gene expres- sion and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells. Int J Hematol. Acknowledgements 2017;106(2):269–81. Not applicable. 12. Hirabayashi S, Butler ER, Ohki K, Kiyokawa N, Bergmann AK, Möricke A, et al. Clinical characteristics and outcomes of B-ALL with ZNF384 rear- Authors’ contributions rangements: a retrospective analysis by the Ponte di Legno Childhood JM contributed to the explanation of laboratory data and the revision of the ALL Working Group. Leukemia. 2021;35(11):3272–7. manuscript. JG wrote the manuscript. BC was responsible for supervising the 13. Shago M, Abla O, Hitzler J, Weitzman S, Abdelhaleem M. Frequency and data analysis. All authors read and approved the final manuscript. outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ Funding ZNF384 gene fusion. Pediatr Blood Cancer. 2016;63(11):1915–21. This work was supported by grants from Key Medical of Jiangsu Province 14. Nishimura A, Hasegawa D, Hirabayashi S, Kanabuchi S, Yamamoto K, Aiga (ZDXKB2016020) and Nanjing Health Science and Technology Development S, et al. Very late relapse cases of TCF3-ZNF384-positive acute lympho- Special Foundation (YKK18262). blastic leukemia. Pediatr Blood Cancer. 2019;66(11):e27891. 15. Reaman GH, Sposto R, Sensel MG, Lange BJ, Feusner JH, Heerema NA, Availability of data and materials et al. Treatment outcome and prognostic factors for infants with acute All data generated or analysed during this study are included in this published lymphoblastic leukemia treated on two consecutive trials of the Chil- article [and its supplementary information files]. dren’s Cancer Group. J Clin Oncol. 1999;17(2):445–55. 16. Cutrona G, Tasso P, Dono M, Roncella S, Ulivi M, Carpaneto EM, et al. CD10 is a marker for cycling cells with propensity to apoptosis in childhood Declarations ALL. Br J Cancer. 2002;86(11):1776–85. 17. Liu YF, Wang BY, Zhang WN, Huang JY, Li BS, Zhang M, et al. Genomic Ethics approval and consent to participate profiling of adult and pediatric B-cell acute lymphoblastic leukemia. Not applicable. EBioMedicine. 2016;8:173–83. Consent for publication Written informed consent was obtained from the patient for publication of Publisher’s Note this case report and any accompanying images. A copy of the written consent Springer Nature remains neutral with regard to jurisdictional claims in pub- is available for review by the Editor-in-Chief of this journal. lished maps and institutional affiliations. Competing interests The authors declare that they have no competing interests. Received: 27 September 2021 Accepted: 28 January 2022 Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : References 1. National Cancer Institute. SEER Cancer Statistics Review, 1975–2020 fast, convenient online submission [Available from: https:// seer. cancer. gov/ statf acts/ html/ alyl. html. thorough peer review by experienced researchers in your field 2. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in rapid publication on acceptance children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995;75(8):2186–95. support for research data, including large and complex data types 3. Nakamoto T, Yamagata T, Sakai R, Ogawa S, Honda H, Ueno H, et al. CIZ, a • gold Open Access which fosters wider collaboration and increased citations zinc finger protein that interacts with p130(cas) and activates the expres- maximum visibility for your research: over 100M website views per year sion of matrix metalloproteinases. Mol Cell Biol. 2000;20(5):1649–58. 4. Jing Y, Li YF, Wan H, Liu DH. Detection of EP300-ZNF384 fusion in patients At BMC, research is always in progress. with acute lymphoblastic leukemia using RNA fusion gene panel sequencing. Ann Hematol. 2020;99(11):2611–7. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Cytogenetics Springer Journals

ZNF384 rearrangement in acute lymphocytic leukemia with renal involvement as the first manifestation is associated with a poor prognosis: a case report

Molecular Cytogenetics , Volume 15 (1) – Feb 14, 2022

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Abstract

Background: Novel fusion genes such as ZNF384, have been identified in B-cell precursor acute lymphoblastic leuke - mia (BCP-ALL) in recent years. Patients harboring ZNF384 rearrangements have a distinctive immunophenotype with weak CD10 and aberrant CD13 and/or CD33 expression. Thus, ZNF384-rearranged ALL is a unique subtype of BCP-ALL. However, research on the prognostic significance of ZNF384 rearrangements has been limited to date, especially in adolescents. Case presentation: We described a 17-year-old adolescent who was diagnosed with ALL and had renal involve- ment as the first manifestation, which was very rare in the existing studies. FISH analysis indicated a rearrangement of ZNF384 according to its probe. The patient had a typical characteristic immunophenotype of ZNF384 rearrange- ment, with CD10 negativity and CD13 and CD33 positivity. She had an unfavorable prognosis because she responded poorly to chemotherapy and developed a relapse shortly after reaching CR. Conclusion: The importance of ZNF384 rearrangements in terms of prognosis remains unclear. We reported an ado- lescent who was diagnosed with ZNF384-rearranged ALL with renal involvement. She underwent different therapies, but her prognosis remained poor. Since ZNF384 rearrangements may act as a prognostic predictor in children or adolescents, early detection based on its characteristic immunophenotype is of great necessity. Keywords: Acute lymphocytic leukemia, ZNF384, Gene rearrangement, Immunophenotype, Prognosis Background accounting for 0.3% of all new cancer cases [1]. ALL usu- Acute lymphocytic leukemia (ALL) is a malignant neo- ally occurs in children and young adults, with the peak plasm in which the differentiation of lymphoid cells is age ranging from 2 to 5 [2]. blocked at an early stage, and there is extensive infiltra - Gene rearrangements and fusions are common in tion in the bone marrow, peripheral blood, and other BCP-ALL, and they play an important role in determin- organs. Over 80% of ALL cases are B-cell precursor ing therapeutic targets and predicting prognosis. With acute lymphoblastic leukemia (BCP-ALL). In 2020, 6,150 the advancement of genome and transcriptome sequenc- new cases of ALL were diagnosed in the United States, ing, novel gene fusions, such as zinc-finger protein 384 (ZNF384) rearrangements have been found. The ZNF384 gene is located on chromosome 12p13. It encodes a zinc *Correspondence: cba8888@hotmail.com finger protein that functions as a transcription factor and Jinlong Ma and Jiaheng Guan contributed equally to this article regulates the expression of matrix metalloproteinases Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China [3]. In ZNF384-rearranged BCP-ALL, the breakpoints © The Author(s) 2022. 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://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ma et al. Molecular Cytogenetics (2022) 15:4 Page 2 of 6 of ZNF384 are typically located in exons 2 and 3, which CD10(+), CD3(−), CD4(−), CD8(−), CD38(+), contain the entire ZNF384 protein that may be respon- CD81(+), HLA-DR(+), CD19(+), CD22(+), CD20(+), sible for the characteristics of the immunophenotype [4, cMPO(−), cCD3(−), cCD79a(+), TDT(+), CD58(+), 5]. Therefore, the presence of ZNF384 rearrangements CD61(−), CD235a(−), and CD11c(−), and these find - should be a hallmark and the diagnostic criterion of a ings are compatible with BCP-ALL (Fig.  3). Next- separate subtype of BCP-ALL since patients harboring generation sequencing (NGS) showed STAG2 gene such rearrangements have a distinctive immunopheno- mutations in the bone marrow, and reverse transcrip- type. This immunophenotype includes weak CD10 and tion-polymerase chain reaction (RT–PCR) showed that aberrant CD13 and/or CD33 expression (6). common fusion genes for BCP-ALL, including TCF3- Recent data have shown that as many as 1% to 6% of PBX1, TCF3-HLF, ETV6-RUNX1 and BCR-ABL, were children and 5% to 15% of adults with BCP-ALL harbor negative. Other less common fusion genes for Ph-like ZNF384 rearrangements [7]. Although the incidence ALL were also negative. is not low, such rearrangements are difficult to detect Her medical history was unremarkable. On physical by conventional karyotype analysis, and there has been examination, the patient had an anemic appearance a lack of research on the prognosis of this rearrange- without ecchymosis. The initial laboratory evaluation ment for a long time. Furthermore, the liver, spleen, and revealed lymphocytosis (2.37 × 10 /l) and moderate lymph nodes are the most common sites of extramedul- anemia (Hb78 g/l, vitamin B12 164  pg/ml, folic acid lary involvement in ALL, with renal involvement being 3.00  ng/ml and serum ferritin 426.7 ug/l). She was relatively uncommon. The unique immunophenotype diagnosed with BCP-ALL with involvement of both of ZNF384 rearrangements helps to diagnose BCP-ALL kidneys. patients with rare sites of extramedullary involvement. After a cycle of the VCDLP regimen, the bone Herein, we report an adolescent case of ZNF384-rear- marrow was obviously hyperplastic and active, and ranged ALL with renal involvement as the first manifes - immature lymphocytes were occasionally observed. tation and poor prognosis. FCM showed the ratio of lymphoblasts was 42% with CD34(+), CD10(−), CD19(+), CD38(+), HLA-DR(+), CD64(−), CD13(+), CD20(−), and CD33(+). Since the Case presentation patient did not achieve remission, a cycle of FLAG sal- A 17-year-old female was admitted to our hospital in vage treatment was administered, and then the patient December 2019 because of increased urine foam and was assessed as complete remission (CR). No lympho- fatigue for 3 weeks. blasts were seen in the bone marrow. FCM showed Laboratory examinations showed protein (3+) and that the ratio of lymphoblasts was 0.8% with CD34(+), occult blood (2+) in urine. The blood urea nitrogen was CD10(−), CD19(+), CD38(+), HLA-DR(+), CD13(+) 5.39  mmol/l, the serum creatinine was 69  μmol/l, and and STAG2 gene mutations. The volume of both kid - the lymphocyte ratio was 62.01%. Kidney color Doppler neys returned to normal according to color Doppler ultrasound showed increased volume in both kidneys ultrasound. After the patient achieved CR, an intrath- as well as enhanced parenchymal echo. Then kidney ecal drug injection was performed for consolidation biopsy was performed, indicating lymphoblastic lym- therapy. Eight months after the continued complete phoma or leukemia with kidney involvement (Fig.  1A remission (CCR), the disease relapsed. A bone marrow and B). Immunohistochemistry showed TdT(+), smear revealed 55.2% lymphoblasts, and FCM showed CD99(+), CD3(−), CD20(part+), CD73(−), PAX5(+), ALL with partial expression of CD33. FISH showed and LCA(part+). Fluorescence in  situ hybridization ZNF384 rearrangement (39%) according to its probe (FISH) of the kidney biopsy sample indicated ZNF384 (Fig.  1F) and positivity for IgH rearrangement (37%). rearrangement (Fig. 1E). Then, bone marrow aspiration The leukemia fusion genes and mutation panels were and biopsy were performed, revealing the disappear- both negative. However, there was no remission in the ance of fat vacuoles and the appearance of immature bone marrow after she was treated with chidamide and lymphoid cells. However, conventional G-banding a dose-adjusted FLAG plus VP chemotherapeutic regi- cytogenetic analysis showed a normal bone marrow men, as well as a highly sensitive treatment, HAD. The karyotype (Fig.  2). A suspected diagnosis of ALL was percentage of lymphoblasts was 14.4% and ZNF384 made. There was extreme lymphocyte proliferation and rearrangement was positive (17.6%) according to FISH. the proportion of lymphoblasts was 50.8% (Fig.  1C and Currently, the patient has been admitted to the hospi- D). Flow cytometry (FCM) of bone marrow revealed tal and is receiving chemotherapy regularly. The details CD34(+), CD117(−), CD33(+), CD64(−), CD13(+), of the treatment process are summarized in Additional CD14(−), CD274(−), TSLPR(−), CD11b(−), IgM(+), file 1 . CD71(−), CD56(+), CD2(−), CD7(−), CD5(−), M a et al. Molecular Cytogenetics (2022) 15:4 Page 3 of 6 Fig. 1 Pathological results of kidney biopsy and bone marrow aspiration smear and results of FISH. A, B The result of kidney biopsy shows increased lymphocytes, indicating lymphoblastic lymphoma or leukemia with kidney involvement (A: HE staining; original magnification, ×400 and B: PAS staining; original magnification, ×400). C The result of Wright-Giemsa staining of the bone marrow smear sample is shown. Bone marrow hyperplasia is extremely active, with lymphoblasts accounting for 50.8% of cells before treatment ( Wright-Giemsa staining; original magnification, ×1000). D Lymphoblasts were negative for myeloperoxidase (red arrow), suggesting the possible diagnosis of acute lymphocytic leukemia (POX staining; original magnification, ×1000). E Fluorescence in situ hybridization (FISH) using a ZNF384 break-apart probe shows ZNF384 rearrangement in the kidney biopsy sample. Recognizable split signals can be seen in the scattered individual cells. The white arrows represent a single red signal and a single green signal (1R1G), which are split signals. The yellow arrow represents a single yellow signal (1Y ), which is a normal signal. 1R1G1Y is a positive signal model for ZNF384 rearrangement. F Describes the ZNF384 rearrangement (39%) in the bone marrow sample, indicating homology with the rearrangement of ZNF384 in the kidney biopsy sample. The two yellow arrows on the left represent two yellow signals, which are negative signals for ZNF384 rearrangement. The white arrows and the yellow arrows on the right are indicative of ZNF384 gene rearrangement (1R1G1Y ) Ma et al. Molecular Cytogenetics (2022) 15:4 Page 4 of 6 Fig. 2 Karyotype analysis of chromosomal G-banding. The G-banded karyotype of bone marrow cells showed a normal karyotype upon admission to our hospital effect of fusion proteins was the inhibition of B-cell dif - Discussion and conclusions ferentiation by introducing EP300, one of the fusion Patients harboring ZNF384 rearrangements are likely to genes, and ZNF384 into mouse pro-B cells, resulting in possess the characteristic immunophenotype of a dull or the stasis of cell differentiation [10, 11]. negative CD10 and aberrant expression of one or more The prognosis of ZNF384 rearrangements in children myeloid antigens. Thus, ZNF384-rearranged ALL is a or adolescents remains unclear. A retrospective study new subtype of leukemia that may be diagnosed as BCP- analyzed a total of 218 ZNF384-rearranged ALL cases, ALL [8]. CD10 was negative in our case, while CD13 with ages ranging from 1 to 25. The 5-year event-free sur - and CD33 were positive, which is consistent with previ- vival (EFS) rate was 85% (95% CI 78–90%), and the 5-year ous studies. The Tokyo Children’s Cancer Study Group overall survival (OS) rate was 91% (95% CI 85–95%) for (TCCSG) reported a similar outcome to ours. TCCSG all patients, suggesting a good outcome [12]. Mary Shago tested 91 samples from BCP-ALL patients, revealing also analyzed a cohort of 240 pediatric patients who were an incidence of a weak or negative expression of CD10, diagnosed with BCP-ALL. Seven of the 240 patients ranging from 0.39 to 67.34% (mean: 19.44 ± 18.23%), were identified to have ZNF384 rearrangements, with and 31.82% and 77.27% expression of CD13 and CD33, an average age of 5.1 years. The EFS ranges from 6 years respectively, in 22 patients with  ZNF384-related fusion 2  months to 9  years 2  months and all patients achieved genes [5]. remission with no relapse [13]. Although a few studies Unlike the mechanism by which subclonal genomic support a generally favorable prognosis in children or variation drives clonal evolution in the disease progres- young adults with ZNF384 rearrangements, others sug- sion of ALL [9], mutational variegation does not deter- gest a poor clinical outcome. A higher recurrence rate mine the immunophenotype for individual patients of over 2% was reported in some pediatric ZNF384 gene harboring ZNF384 rearrangements, and immunophe- fusion cases [5]. Nishimura reported two pediatric TCF3- notypic aberrancy arises from inherent lineage plasticity ZNF384-positive patients who developed disease relapse [8]. Moreover, fusion partners for ZNF384 are commonly more than 10  years after diagnosis [14]. Additionally, involved in BCP-ALL, which is responsible for leukemia CD10 negativity was found to be an independent adverse development. Preclinical studies found that the initial M a et al. Molecular Cytogenetics (2022) 15:4 Page 5 of 6 Fig. 3 The results of flow cytometry. The flow cytometry results indicated acute lymphocytic leukemia. A The proportion of primary cells was 68.45% according to the SSC/CD45 gating. B The CD22 fraction is shown as 22.8%. C CD19 was positive, with a proportion of 81.1%, and CD10 was positive, with a proportion of 20.9%. D CD34 was positive, with a proportion of 98.2%, and CD13 was positive, with a proportion of 55.8%. E CD20 was positive, with a proportion of 35.0%. F CD33 was positive, with a percentage of 69.8% prognostic factor in ALL because CD10-negative lymph- In conclusion, we report a BCP-ALL case with a oblastic leukemia cells had lower cycling capacities and ZNF384 rearrangement. The adolescent patient had were resistant to apoptosis [15, 16]. A cohort study in very rare renal involvement as the first manifestation. China investigating 111 pediatric patients with BCP-ALL However, she showed a very typical immunopheno- revealed that leukemic cells from patients with ZNF384 type of ZNF384-rearranged ALL with CD10 negativity fusions were more likely to be CD10-negative than those and CD13 and CD33 positivity. She responded poorly from other pediatric patients (18.8% vs. 2.9%, P = 0.02) to chemotherapy and developed a relapse shortly after (17). This finding may explain why children with ZNF384 achieving CR. Her bone marrow karyotype was normal, rearrangements have unfavorable outcomes. The ado - which may suggest that the ZNF384 rearrangement- lescent patient in our case had the distinct immunophe- related abnormal karyotype was under the detection notype of CD10 negativity, and she developed disease limit of conventional G-banding. This indicates that more relapse only eight months after she reached CR despite sensitive methods, such as FISH, should be used. Owing receiving consistent consolidation chemotherapy. She to the low detection rate and variety of treatment pro- also had poor responses to multiple chemotherapeutic tocols from institution to institution, the statistical sig- therapies, necessitating frequent adjustments to more nificance of clinical outcomes in children or adolescents effective and powerful regimens. Our report supple - with ZNF384 rearrangements has not been analyzed thus ments the unfavorable outcomes of adolescent patients far. However, it has been linked to an unfavorable prog- with ZNF384 rearrangements in the existing literature nosis in some small studies, but this still needs to be rep- and supports the view that ZNF384 rearrangements are licated on a larger scale to be confirmed. Furthermore, correlated with a poor prognosis. However, larger-scale ZNF384 break-apart probes are not commonly included multicenter studies are required to evaluate the exact in screening leukemia translocations, which could cause prognosis of ZNF384 rearrangements, especially in chil- a delay in diagnosis and treatment. Therefore, we suggest dren or adolescents. that when the rearrangement of ZNF384 is suspected Ma et al. Molecular Cytogenetics (2022) 15:4 Page 6 of 6 5. Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura based on its characteristic immunophenotype, it should K, et al. ZNF384-related fusion genes define a subgroup of childhood be tested and confirmed as soon as possible. B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica. 2017;102(1):118–29. 6. Gocho Y, Kiyokawa N, Ichikawa H, Nakabayashi K, Osumi T, Ishibashi T, Abbreviations et al. A novel recurrent EP300-ZNF384 gene fusion in B-cell precursor ALL: Acute lymphocytic leukemia; BCP-ALL: B-cell precursor acute lympho- acute lymphoblastic leukemia. Leukemia. 2015;29(12):2445–8. blastic leukemia; ZNF384: Zinc-finger protein 384; FISH: Fluorescence in situ 7. Lilljebjörn H, Fioretos T. New oncogenic subtypes in pediatric B-cell hybridization; FCM: Flow cytometry; NGS: Next generation sequencing; precursor acute lymphoblastic leukemia. Blood. 2017;130(12):1395–401. RT-PCR: Reverse transcription-polymerase chain reaction; CR: Complete remis- 8. Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, et al. The sion; CCR : Continued complete remission; TCCSG: The Tokyo Children’s Cancer genetic basis and cell of origin of mixed phenotype acute leukaemia. Study Group; EFS: Event-free survival; OS: Overall survival. Nature. 2018;562(7727):373–9. 9. Ma X, Edmonson M, Yergeau D, Muzny DM, Hampton OA, Rusch M, et al. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute Supplementary Information lymphoblastic leukaemia. Nat Commun. 2015;6:6604. The online version contains supplementary material available at https:// doi. 10. Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F, Kojima S, Ueno T, et al. Recur- org/ 10. 1186/ s13039- 022- 00583-4. rent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet. 2016;48(5):569–74. 11. Yaguchi A, Ishibashi T, Terada K, Ueno-Yokohata H, Saito Y, Fujimura J, et al. Additional file 1. EP300-ZNF384 fusion gene product up-regulates GATA3 gene expres- sion and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells. Int J Hematol. Acknowledgements 2017;106(2):269–81. Not applicable. 12. Hirabayashi S, Butler ER, Ohki K, Kiyokawa N, Bergmann AK, Möricke A, et al. Clinical characteristics and outcomes of B-ALL with ZNF384 rear- Authors’ contributions rangements: a retrospective analysis by the Ponte di Legno Childhood JM contributed to the explanation of laboratory data and the revision of the ALL Working Group. Leukemia. 2021;35(11):3272–7. manuscript. JG wrote the manuscript. BC was responsible for supervising the 13. Shago M, Abla O, Hitzler J, Weitzman S, Abdelhaleem M. Frequency and data analysis. All authors read and approved the final manuscript. outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ Funding ZNF384 gene fusion. Pediatr Blood Cancer. 2016;63(11):1915–21. This work was supported by grants from Key Medical of Jiangsu Province 14. Nishimura A, Hasegawa D, Hirabayashi S, Kanabuchi S, Yamamoto K, Aiga (ZDXKB2016020) and Nanjing Health Science and Technology Development S, et al. Very late relapse cases of TCF3-ZNF384-positive acute lympho- Special Foundation (YKK18262). blastic leukemia. Pediatr Blood Cancer. 2019;66(11):e27891. 15. Reaman GH, Sposto R, Sensel MG, Lange BJ, Feusner JH, Heerema NA, Availability of data and materials et al. Treatment outcome and prognostic factors for infants with acute All data generated or analysed during this study are included in this published lymphoblastic leukemia treated on two consecutive trials of the Chil- article [and its supplementary information files]. dren’s Cancer Group. J Clin Oncol. 1999;17(2):445–55. 16. Cutrona G, Tasso P, Dono M, Roncella S, Ulivi M, Carpaneto EM, et al. CD10 is a marker for cycling cells with propensity to apoptosis in childhood Declarations ALL. Br J Cancer. 2002;86(11):1776–85. 17. Liu YF, Wang BY, Zhang WN, Huang JY, Li BS, Zhang M, et al. Genomic Ethics approval and consent to participate profiling of adult and pediatric B-cell acute lymphoblastic leukemia. Not applicable. EBioMedicine. 2016;8:173–83. Consent for publication Written informed consent was obtained from the patient for publication of Publisher’s Note this case report and any accompanying images. A copy of the written consent Springer Nature remains neutral with regard to jurisdictional claims in pub- is available for review by the Editor-in-Chief of this journal. lished maps and institutional affiliations. Competing interests The authors declare that they have no competing interests. Received: 27 September 2021 Accepted: 28 January 2022 Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : References 1. National Cancer Institute. SEER Cancer Statistics Review, 1975–2020 fast, convenient online submission [Available from: https:// seer. cancer. gov/ statf acts/ html/ alyl. html. thorough peer review by experienced researchers in your field 2. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in rapid publication on acceptance children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995;75(8):2186–95. support for research data, including large and complex data types 3. Nakamoto T, Yamagata T, Sakai R, Ogawa S, Honda H, Ueno H, et al. CIZ, a • gold Open Access which fosters wider collaboration and increased citations zinc finger protein that interacts with p130(cas) and activates the expres- maximum visibility for your research: over 100M website views per year sion of matrix metalloproteinases. Mol Cell Biol. 2000;20(5):1649–58. 4. Jing Y, Li YF, Wan H, Liu DH. Detection of EP300-ZNF384 fusion in patients At BMC, research is always in progress. with acute lymphoblastic leukemia using RNA fusion gene panel sequencing. Ann Hematol. 2020;99(11):2611–7. Learn more biomedcentral.com/submissions

Journal

Molecular CytogeneticsSpringer Journals

Published: Feb 14, 2022

Keywords: Acute lymphocytic leukemia; ZNF384; Gene rearrangement; Immunophenotype; Prognosis

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