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Relation of BAALC and ERG Gene Expression with Overall Survival In DOI:http://dx.doi.org/10.7314/APJCP.2015.16.17.7875 BAALC and ERG Genes as Prognostic Factors in Adult Myeloid Leukemia Patients, Egypt RESEARCH ARTICLE Relation of BAALC and ERG Gene Expression with Overall Survival in Acute Myeloid Leukemia Cases Reham A Rashed1*, Dalia Y Kadry1, Maha EL Taweel1, Nahed Abd El Wahab1, Thoreya Abd El Hameed2 Abstract Background: The objectives of this study were to evaluate the expression of brain and acute leukemia, cytoplasmic (BAALC) gene and erythroblast transformation-specific related gene (ERG) in de novo cases of acute myeloid leukemia (AML) and identify roles in disease progression and outcome. Materials and Methods: This study included 50 newly diagnosed AML patients, along with 10 apparently healthy normal controls. BAALC and ERG expression was detected in the bone marrow of both patients and controls using real-time RT-PCR. Results: BAALC and ERG expression was detected in 52% of cases but not in any controls. There was a statistically significant correlation between BAALC and ERG gene expression and age (p- value =0.004 and 0.019, respectively). No statistical significance was noted for sex, lymphadenopathy, hepatomegaly, splenomegaly, other hematological findings, immunophenotyping and FAB sub-classification except for ERG gene and FAB (p-value=0.058). A statistical significant correlation was found between response to treatment with ERG expression (p-value=0.028) and age (p-value=0.014). A statistically significant variation in overall survival was evident with patient age, BM blast cells, FAB subgroups, BAALC and ERG expression (p-value= <0.001, 0.045, 0.041, <0.008 and 0.025 respectively). Conclusions: Our results suggest that BAALC and ERG genes are specific significant molecular markers in AML disease progression, response to treatment and survival. Keywords: BAALC - ERG - AML - RT-PCR Asian Pac J Cancer Prev, 16 (17), 7875-7882 Introduction indefinite self-renewal in a manner analogous to a stem cell, escape from programmed cell death, inhibition of Acute myeloid leukemia (AML) is a cytogenetically differentiation, aberrant cell cycle checkpoint control, and molecularly heterogeneous disease characterized genomic instability and multi-organ dissemination of by clonal proliferation of myeloid precursors and leukemic cells (Lichtman and Sternberg, 2005). maturation arrest, with accumulation of acquired genetic The brain and acute leukemia, cytoplasmic (BAALC), alterations in hematopoietic progenitor cells that disturb which maps on chromosome 8 at 8q22.3, was originally normal mechanisms of cell growth, proliferation and observed in the neuroderm and its expression was differentiation (Dohner 2005). The precise molecular reported as a hematopoietic precursor, such as the early origins of AML are unknown. The pathophysiologic hematopoietic cells of cluster of differentiation 34+( mechanisms are multiple, act in concert, and probably Baldus et al., 2003). BAALC expression was higher in are distinct in different types of AML. Inherited genetic bone marrow compared to blood. In addition, high levels predisposition and environmental mutagens such as of BAALC expression were present in leukemic blasts in radiation, drugs and other toxins all play a role in the subsets of acute lymphoblastic leukemia (ALL) and AML development of AML (Solomon and Malkovska, 2005). patients with a normal karyotype (Bienz et al., 2005), it Leukemogenesis in AML is a heterogeneous, multistep may act as an adverse prognostic factor through prompting process, single genetic change is insufficient to cause AML proliferation and inhibiting apoptosis in leukemia cells by itself, and at least two different mutations must occur (Bing et al., 2012). in the hematopoietic progenitor cell to transform it into The site and cellular mechanism(s) of the effects of a malignant cell initiating the development of a clonal the BAALC gene are unclear, thereby possibly resulting AML blast population (Mrozek et al., 2007). The resulting in differentiation failure caused by cell shape, motility molecular alterations disrupt almost every facet of cell and adhesion in the association between cells (Tanner transformation. These processes include the inappropriate et al., 2001). Subsequent research has shown that the proliferation in the absence of normal growth signals, highly expressed BAALC gene is associated with minimal 1Clinical Pathology, 2Medical Oncology Department, Medicine, National Cancer Institute, Cairo, Egypt *For correspondence: [email protected] Asian Pacific Journal of Cancer Prevention, Vol 16, 2015 7875 Reham A Rashed et al residual disease, which leads to a low complete remission with t(15;17), t(8;21), inv.(16) or t(16;16), and some (CR) rate and overall survival (OS). cases of erythroleukemia. Myeloblasts, monoblasts, The ERG (ETS related gene 1) gene belongs to the and megakaryoblasts are included in the blast count. In erythroblast transformation-specific (ETS) family of AML with monocytic or myelomonocytic differentiation, transcription factors, and is located on chromosome monoblasts and promonocytes, but not abnormal 21q22.2 (Oikawa and Yamada, 2003). ERG and other monocytes, are counted as blast equivalents. Erythroblasts members of the same family are downstream regulators are not counted as blasts except in the rare instance of pure of mitogenic signal transduction pathways. They are key erythroid leukemia. regulators of embryonic development, cell proliferation, Pretreatment BM samples were centrally collected differentiation, angiogenesis, inflammation, and apoptosis and stored. Samples were enriched for the blast fraction (Loughran et al., 2008). by density-gradient centrifugation (Ficoll-Hypaque Plus; ERG, plays an important role in early hematopoiesis Amersham Biosciences, Uppsala, Sweden) and stored in and hematopoietic stem cell (HSC) maintenance (Taoudi liquid nitrogen. et al., 2011). ERG is also part of fusion proteins in solid Immunophenotyping of fresh bone marrow samples tumors such as prostate cancer (Klezovitch et al., 2008), was performed for all cases using flow cytometric Ewing Sarcoma (Sorensen et al., 1994) and in acute analysis (Partec III from DAKO cytomation) (on routine myeloid leukemia (AML) (Kong et al., 1997). basis), on marrow blast cells with a panel of monoclonal In acute leukemia, high ERG mRNA expression antibodies, purchased from DAKO ( Denmark), including levels are an independent prognostic factor. Studies have FITC and PE conjugated CD13, CD33 and MPO. demonstrated that increased ERG expression is associated Specific isotype controls for FITC and PE conjugated with poor prognosis in cytogenetically normal AML (Eid monoclonal antibodies were used. Results were expressed et al., 2010) and in adult T-ALL (Baldus et al., 2006). as percentage of cells showing positive expression. In this study we aimed to evaluate the expression of BAALC and ERG genes in leukemic cells from newly RNA Isolation and Complementary DNA Synthesis diagnosed acute myeloid leukemia patients, and correlate Pretreatead BM samples were available from 50 data with their significance in disease progression, AML patients and 10 healthy controls. Bone marrow response to treatment and survival as well as their potential mononuclear cells (BMMCs) were extracted from 1-2 ml use as target molecules in therapy. EDTA blood cells, (they were obtained by gradient density centrifugation using Ficoll-Hypaque 1077 (Sigma). Cell Materials and Methods pellets were kept at -80°C until RNA extraction was performed. Extraction of total RNA from mononuclear This study was carried out on 50 newly diagnosed cells was carried out using the QIA-amp RNA blood acute myeloid leukemia cases, who presented to the Mini Kit (QIAGEN, Hilden, Germany) following the medical oncology clinics, National Cancer Institute, manufacturer’s instructions. The concentration and purity Cairo University, during the period from February 2010 to of RNA was measured at 260 & 280 & 230 nm using Nano March 2012 with ten healthy age and sex matched controls Drop 2000/2000c Spectrophotometer (Thermo Scientific, were included in the study. USA). Ratio of A260/A280 = 1.8 - 2.1 and A260/A230 = A Written informed consent was approved by the 1.8 - 2.1 indicates highly pure RNA. Institutional Review board (IRB) ethical committee of the Extracted RNA was reverse transcribed into NCI which follows the rules of Helsinki IRB was obtained Complementary DNA (c DNA) using TaqMan® RNA from each patient before starting the data collection. reverse Transcription Kit (Applied Bio-system, USA) For the sake of patient’s privacy, they were given code according to the TaqMan RNA Assay protocol. The PCR numbers. reactions were carried out in a total volume of 20ul (10ul mix+ 10ul extracted RNA), the thermal cycle reaction was Morphological and immunophenotypic analysis as follows: 10 minutes at 25oC (for incubation), 37oC for 2 Morphologic analysis of bone marrow (BM) smear hours for reverse transcription, 85oC for 5 seconds to stop preparations was carried out at the Hematology Unit of the reaction. The main PCR cycles were repeated 40 times. the Clinical Pathology Department at the National Cancer Institute, Cairo University, Egypt. Quantitative real-time reverse - transcription - polymerase A bone marrow aspirate is part of the routine diagnostic chain reaction (RT-PCR) amplification of BAALC, ERG work-up of a patient with suspected AML. The panel Complementary DNA and amplification of nucleic considers a marrow trephine biopsy optional, but it should acid by
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