T-ALL with TEL/AML1 Translocation, Aberrant Expression of CD19 and 33: Case Report and Literature Review

We herewith introduce a 9-year-old boy presenting with leukocytosis, anemia and high lymphoblast count who had a pale complexion as well as weight loss. His cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XY karyotype with t (12; 21) (p12; q22), which was confi rmed by DNA sequencing. Flowcytometry assay detected aberrant B lymphocyte and myeloid CD markers such as CD19 (22.0%) and CD33 (20.5%), respectively. To our knowledge, this is the fi rst case of a patient initially diagnosed as TEL/AML1 transcript positive T-ALL expressing CD19 and CD33 markers. The present article also highlights the need for molecular gene rearrangement studies to determine the precise lineage of ambiguous ALL clones. Case Report T-ALL with TEL/AML1 Translocation, Aberrant Expression of CD19 and 33: Case Report and Literature Review Kave Jasseb1, Maria Kavianpour1, Javad Mohammadi Asl2, Zahra Shahpouri Arani1, Vahid Fallah Azad3, Mansoureh Haghighi3 and Najmaldin Saki1* 1Health Research Institute, Thalassemia and Hemoglobinopathies Research Center, Ahvaz Jundishapur University of Medical Sciences, Iran 2Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Iran 3Research Department, Mahak’s Pediatric Cancer Treatment and Research Center, Tehran, Iran Dates: Received: 02 December, 2016; Accepted: 13 December, 2016; Published: 14 December, 2016 *Corresponding author: Najmaldin Saki, Health Research Institute, Thalassemia & Hemoglobinopathies Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, Tel: +98.6133738317: Fax: +98.6133738330; E-mail:


Introduction
T-Acute lymphoblastic leukemia (T-ALL) is one of the most important hematologic malignancies occurring due to clonal proliferation of T lymphocytes in approximately 15-25% of ALL patients [1]. In comparison with B-ALL patients, those suffering from T-ALL are at risk of increased leukocyte count (WBC>20×10 9 /L), organomegaly, enlarged mediastinal mass and central nervous system (CNS) involvement [2]. Immunophenotype studies have enabled the differentiation between T-and B-cells. Cluster of differentiation (CD) molecules 79a and CD22 as well as cCD3 and TCR are specifi c for B-cells and T-cells, respectively. Myeloid markers such as CD13, CD33 and myeloperoxidase (MPO) may be observed in different ALL types, and MPO expression can be a marker of ambiguous lineage leukemia, for example in T or B ALL with aberrant expression of myeloid lineage markers [3].
Immunophenotype study of this translocation revealed the presence of CD10, CD19 and CD22, precursor B-cell phenotype as well as other markers of this cell line such as HLA-DR, CD10, CD13, CD19, CD24, CD33, CD34, CD40, CD45 and CDw65 but the absence of CD9, CD20 and CD86 [6][7][8]. In general, t(12; 21) (p12; q22) is observed in common ALL, pre-B-ALL (BCP-ALL) and rarely in pro-B-ALL, and is raised as the most common gene rearrangement in childhood BCP-ALL [9,10]. In the study of Ma et al, one of the patients had T-ALL, which has been the only report of t(12; 21) translocation in T-ALL [11].
The presence of t(12; 21) translocation usually involves a favorable prognosis and response to treatment since the majority of TEL/AML1 positive patients show non-invasive clinical symptoms, non-hyperdiploid DNA content and younger than 10 years of age [12][13][14]. Favorable prognosis resulting from this fusion can be demonstrated with its low incidence in recurrent cases (8.9% and 10%) in addition to high percentage of event-free survival (EFS) (approximately 89-100%) [13,15,16]. Detection of TEL/AML1 gene fusion is considered an important marker for prognosis of response to treatment. In this study, we have investigated a patient with diagnosis of T-ALL having t(12;21) (p12; q22) translocation, which has not been reported except for one case. (68%), CD19 (22%), CD34 (37.5%) and cCD79a (15.2%). The BM sample showed t (12:21), and the presence of TEL/AML1 fusion was confi rmed by molecular methods and sequencing. After purifi cation RNA and cDNA production, the two steps of nestedpolymerase chain reaction (Nested-PCR) were performed and the primer sequences are listed in Table.1. Then, PCR products were electrophoresed on acrylamide gel. Amplification of TEL/ AML1 transcript was used as the positive and negative control. PCR product of TEL/AML1 transcript was sequenced using ABI PRISM 3730 DNA Analyzer (Applied Biosystems, Foster City, CA) (Figure 2).

Case Presentation
The patient received Vincristine (VCR), L-Asparaginase (L-ASP), Prednisolone and Daunorubicin as induction and was discharged with improved health status. For complete remission he received Prednisolone, 6-Mercaptopurin, Vincristine and Methotrexate.

Discussion
Translocation (12; 21) (p12; q22) is one of the most important genetic lesions occurring in ALL. This fusion is caused by integration of two critical genes involved both in hematopoiesis and leukemogenesis. Cytogenetic and molecular studies such as fl uorescent in situ hybridization (FISH) and real-time PCR (RT-PCR) have enabled the detection of this translocation and its subsequent fusion [13,15]. After detection of this translocation by Shurtleff et al., TEL/AML1 fusion was introduced as an ''excellent prognosis'' marker, although 5-year event free survival in patients harboring this fusion was not signifi cantly different from other patients who were negative for it [6]. In general, the presence of this translocation places the patients in a separate group with low risk for recurrence and better response to treatment. According to different studies, it is believed that the presence of TEL/ AML1 fusion is indicative of B-ALL. In addition, presence of this fusion is associated with lower leukocyte count and lower age (1-10 years), which are considered as favorable prognostic factors [17].
Study of immunophenotype is an important biological parameter in patient's survival and prediction of response to treatment. Aberrant phenotype occurs with the development of lymphoid and myeloid markers in myoblasts or lymphoblasts, and has an overall frequency of 80% in both ALL and AML [18]. Specifi c T-lymphoid markers include CD1a, CD3, CD4, CD5, CD7 and CD8 but B-lymphoid antigens are CD10, CD19, CD22, and cytoplasmic CD79a. MPO, CD13 and CD33 are also common myeloid markers. CD34, HLA-DR, and TdT are used to investigate the precursor cells ( Table 2). The world health organization defi nes Pre-T ALL as a malignancy often occurring in TdT-positive males, which is sometimes associated with the expression of CD10, CD79a and cCD3 markers. Myeloid markers (CD13 and CD33) are "often present" but CD117 is rarely observed [19]. In the study of Suggs et al, the expression of CD13 and CD33 was reported in 24% of pre-T ALL cases, who were male patients aged 13-25 years [20]. The study of Yao et al, dealt with a patient suffering from T-cell lymphoma with aberrant expression of CD79a and CD20. The patient had both B-and T-cell markers and was deceased six months after initial diagnosis due to poor prognosis. This study also showed that the presence of a marker is not specifi c to a certain disease type and a panel of antibodies should be used for further investigation [21], ( Table 2). In the study of Forestier et al., 1140 children aged 1-15 years were diagnosed with B-ALL from 1992 to 2004, from which 288 cases were positive for t(12;21) [8]. However, in the study of MA et al., who simultaneously investigated different ALL types like common, pre-B, early Band T-for presence of t (12;21), only one case of T-ALL (7.5%) expressed this fusion [11].
In this study, the patient showed t(12;21) despite the presence of T-cell immunophenotype. The favorable prognosis of other ALL types harboring this translocation was also reported in this patient and we observed a good response to treatment in him until under follow up. As a result, the presence of t(12;21) may be observed in various ALL subgroups, which rules out its specifi city for B-cells. Aberrant expression of B-cell and myeloid lineage markers in T-ALL complicates