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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 37  |  Issue : 4  |  Page : 246-251

Study of transcription factor CCAAT/enhancer binding protein-α (C/EBPα) in adult patients with acute lymphoblastic leukemia


1 Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Clinical Pathology Departments, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission01-Jun-2012
Date of Acceptance03-Jul-2012
Date of Web Publication21-Jun-2014

Correspondence Address:
Gihan M. Kamal
Internal Medicine Department, Faculty of Medicine, Ain Shams University, P.O. Box 1156, Abbassia, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000419281.71909.2c

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  Abstract 

Background

Leukemic stem cells have self-renewal property. Identification of genes or signaling pathways involved in self-renewal of leukemic stem cells will promote the development of more effective treatment for acute leukemias.

Objectives

To assess the prognostic significance of the CCAATT/enhancer binding protein-α (C/EBPα) transcription factor in primary adult patients with acute lymphoblastic leukemia (ALL) and its correlation to prognosis and response to therapy.

Participants and methods

Forty adult patients with ALL (23 pre-B ALL, one pro-B ALL, four mature B ALL, and 12 T ALL) were recruited from the Hematology Department, Ain Shams University, compared with 25 age-matched and sex-matched healthy controls. All patients were subjected to a complete blood count, blood chemistry, bone marrow (BM) examination, immunophenotyping, cytogenetics, and assessment of the C/EBPα level using real–time PCR at presentation and at D28 of treatment. Patients were followed over a period of 24 months (1–24 ms).

Results

Compared with controls, patients with ALL at presentation and at follow-up showed a highly significant difference in C/EBPα (P<0.01), whereas there was no significant difference between B ALL and T ALL. Patients who achieved remission showed a significant increase in C/EBPα after treatment. There was no significant correlation between C/EPBα and other prognostic factors in ALL, except with the Philadelphia chromosome; there was a significantly negative correlation at diagnosis and at follow-up.

Conclusion

Deficient C/EBPα among patients with ALL may contribute toward its pathogenesis and remission is associated with a significant increase in the C/EBPα level. C/EBPα is an independent prognostic factor and its measurement helps to predict response and contributes significantly toward better management decisions.

Keywords: acute lymphoblastic leukemia, CCAATT/enhancer binding protein-α, prognosis


How to cite this article:
Asfour IA, Elhagracy RS, Kamal GM, Nabih NA, Abass AA, Radwan RA. Study of transcription factor CCAAT/enhancer binding protein-α (C/EBPα) in adult patients with acute lymphoblastic leukemia. Egypt J Haematol 2012;37:246-51

How to cite this URL:
Asfour IA, Elhagracy RS, Kamal GM, Nabih NA, Abass AA, Radwan RA. Study of transcription factor CCAAT/enhancer binding protein-α (C/EBPα) in adult patients with acute lymphoblastic leukemia. Egypt J Haematol [serial online] 2012 [cited 2020 Apr 10];37:246-51. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/246/134972


  Introduction Top


Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates from one single hematopoietic precursor committed to B-cell or T-cell linage 1. Although more than 90% of adult patients with ALL achieve complete remission by morphology, the relapse rate is frequent and cure rates until recently have been in the range of 30–40% 2. This may be related to the fact that these leukemic cells carry numerous genetic alterations with specific prognostic values. Therefore, their description is an important part of the diagnostic procedures not only for the choice of a risk-adapted treatment but also because some of the altered proteins can be subject to highly efficient target therapy 1. In a continuing effort to identify these genetic abnormalities, several studies have confirmed the hypothesis that a number of leukemic cases are not associated with constant translocation but with other genetic mutations 3. The types of genetic mutations identified in ALL can be aberrant expressions of proto-oncogenes, chimeric protein kinases, and transcription factors resulting from chromosomal translocations and hyperdiploidy of more than 50 chromosomes 4. Transcription factors regulate gene expression by controlling the transcription of specific genes or gene families 5. CCAATT/enhancer binding protein-α (C/EBPα) is the founding member of a group of six basic region leucine zipper (bZip) transcription factors 6. C/EBPα regulates the balance between cell proliferation and differentiation in hematopoietic and nonhematopoietic tissues 7. It is a critical transcription factor involved in cell cycle arrest and induction of lineage-specific differentiation genes in several cell types 8. Several human tumor types show a reduction in the levels of C/EBPα, indicating that C/EBPα is a tumor suppressor 9. Leecharendkeat et al. 10 have identified the C/EBPα gene as the target of genetic alterations in acute myeloid leukemia (AML). In ALL C/EBPα is found to be activated in human pre-B ALL by juxtaposition to the immunoglobulin gene enhancer upon the t (14;19)(q32;q13) chromosomal rearrangement 11. This indicates that not only loss but also gain of function of C/EBPα has leukemogenic potential 12.

Aim of the work

To evaluate the prognostic value of C/EBPα in primary adult patients with ALL and to assess its correlation with the known diagnostic and prognostic factors in ALL.


  Patients and methods Top


The present study was carried out on 65 patients, who were subdivided into group A, which included 40 adult patients with newly diagnosed ALL [22 patients (55%) were women, whereas 18 patients (45%) were men] ranging in age from 18 to 55 years. An informed consent was obtained from all patients according to the protocols approved by the local ethical committee, Ain Shams University. Group B included 25 age-matched and sex-matched healthy controls. All patients received an induction chemotherapy protocol in the form of doxorubicin 40 mg/m2 intravenously ‘D1, 8, 15, 22’+vincristine 1.4 mg/m2 intravenously ‘D 1, 8, 15, 22’+dexamethasone 12 mg intravenously ‘D1–28’+asparaginase 5000 IU/m2 intravenously ‘D 15–28.’ Patients who were diagnosed with mature B ALL received induction chemotherapy with the (hyper-CVAD) protocol for a total of eight induction and consolidation cycles. Courses 1, 3, 5, and 7 included cyclophosphamide 300 mg/m2 twice daily intravenously ‘D 1–3’+vincristine 2 mg intravenously ‘D 4+11’+doxorubicin 50 mg/m2 intravenously ‘D4’+dexamethasone 40 mg intravenously ‘D 1–4.’ Courses 2, 4, 6, and 8 included methotrexate 1000 mg/m2 intravenously (24 h inf.) D1+cytarabine 3000 mg/m2 twice daily intravenously ‘D2+3.’ All courses with granulocyte colony stimulating factor support were repeated every 3 weeks 13.

Only seven patients failed to achieve complete remission after first induction chemotherapy, who received the hyper-CVAD protocol for reinduction. Patients were followed up until they finished the first induction chemotherapy and day 28 BM aspirate and C/EBP were reevaluated.

All patients were subjected to the following:

Detailed history and examination particularly for pallor, purpura, hepatosplenomegaly, and lymphadenopathy.

Complete blood count using an automated coulter counter. With examination of Leishman-stained peripheral blood (PB), with a focus on the differential leukocytic count and assessment of blast cell count and morphology.

Liver and kidney function tests, lactate dehydrogenase (LDH), and serum uric acid.

BM aspiration and examination of Leishman-stained films, with a focus on percentage of blast, BM cellularity, and dysplastic changes, was performed at diagnoses and after induction therapy with myeloperoxidase-stained PB and BM smears.

Immunophenotyping of BM aspirate was carried out using EPICS XL coulter flow cytometry (Coulter Electronics Inc., Hialeah, Florida, USA). The panel of monoclonal antibodies included common progenitor markers (CD34, HLADR), myeloid markers (CD13, CD33, CD14, CD15, CD61, and MPO), B-cell lymphoid markers (CD10, CD19, CD20, CD79a, and CD79b), and T-cell lymphoid markers (CD2, CD3, CD5, and CD7). According to immunophenotyping, ALL cases were classified into B and T lymphoblastic leukemia. B lymphoblastic leukemia was subdivided into pro-B ALL, pre-B ALL, and mature B ALL.

Conventional cytogenetic analysis using G banding was carried out at diagnosis on BM aspirate ‘standard karyotyping’ and fluorescence in-situ hybridization to detect the Philadelphia (Ph) chromosome.

Measurement of C/EBPα using real-time PCR (RT-PCR) on the PB sample at presentation and after induction chemotherapy.

Analytical methods of real-time polymerase chain reaction and gene assay

Venous blood samples of 10 ml were drawn under aseptic conditions into sterile tubes coated by preservative-free heparin for peripheral blood mononuclear layer (PBML) separation for RT-PCR and gene assay.

Procedures

(1) Sample preparation.

(2) Reverse transcription to generate cDNA.

(3) RT-PCR amplification for the target gene (C/EBPα) using the Stratagene Mx3000P thermocycler (Stratagene, La Jolla, USA).

Sample preparation

(a) Separation of PBML: PBML separation was carried out by the Ficoll-Hypaque centrifugation gradient. The pelleted cell was suspended in 500 µl PBS for the RNA extraction, which was carried out on the same day as separation. RNA extraction was carried out using the RNA Isolation Kit (QIAGEN, Valencia, California, USA).

Reverse transcription of the target RNA to generate complementary DNA

Reverse transcription done using high-capacity cDNA reverse transcription kits (Applied Biosystems, Foster City, California, USA). To each reaction tube, the following reagents were added: 2 μl of reaction buffer, 0.8 µl of dNTP’s mix, 1 µl of multiscribe reverse transcriptase, 2 µl of random hexamer, 4.2 µl of free nuclease water, and10 µl of extracted RNA. We mixed the reaction components gently and then RT-PCR was carried out using the following protocol after placing the sample tubes in the thermal cycler: first step at 25° for 10 min, second step, the RT step, at 37°C for 120 min, followed by stopping of RT at 85°C for 5 s, and finally a holding step at 4°C.

Real-time polymerase chain reaction amplification for the target gene

We used TaqMan Gene Expression Assays supplied by Applied Biosystems, Assay ID Hs00269972_s1*.

TaqMan Gene Expression Assays tube contained two unlabeled primers (20× stock concentration was 18 μmol/l per primer) that were reconstituted with distilled water to 10 pmol/μl. In addition to, one 6-FAM dye-labeled, TaqMan MGB probe (20 x stock concentration is 5 mmol/l). The probe was reconstituted with distilled water and adjusted to 5 pmol/μl. The kit also included 2× TaqMan Gene Expression Master Mix and a TaqMan GAPDH assay tube, which contained GAPDH primers and probe, and was used as an internal normalization control for validation of each sample.

For each sample, we pipetted 1.25 μl of TaqMan Gene Expression Assays, 1.25 μl of TaqMan GAPDH assay, 12.5 μl of TaqMan Gene Expression Master Mix, 5 μl of RNase-free water, and 5 μl of cDNA template (1–100 ng) into a nuclease-free 1.5 ml microcentrifuge tube. We mixed the reaction components gently and then PCR was carried out applying the following protocol after placing the sample tubes in the thermal cycler: First step at 48° for 30 min, second step of initial denaturation at 95° for 10 min, third step of denaturation at 95° for 15 s, and primer annealing and extension at 60° for 1 min. This third step was repeated for 40 cycles, followed by hold at 4°C.

Analysis of the results

We used the comparative CT method to analyze our data as follows:

First, we determined the ΔCT of the test:

CT=CT (test)−CT (GAPDH test)

We determined the ΔCT of the calibrator:

ΔCT=CT (calibrator)−CT (GAPDH calibrator)

ΔΔCTCT (unknown)−ΔCT (calibrator)

Gene expression= 2-ΔΔCT

Statistical analysis

Statistical analysis was carried out using SPSS 15 software package (SPSS Inc., Chicago, Illinois, USA) in a Windows 7 operating system. Qualitative data parameters were presented in the form of frequency and percentage; quantitative data parameters were presented in the form of mean and median±SD. Comparative analysis was carried out using the Mann–Whitney U-test (Z value) for comparisons between two independent samples with a nonparametric distribution or Student’s t-test (t value) for comparisons between two independent samples with a normal distribution. Correlations between variables were determined either by Pearson’s correlation (r value) for normally distributed data, Spearman’s rank correlation (&rgr; value), or point-biserial correlation (rpb) for correlations between continuous and dichotomous variables. An receiver-operating characteristic curve was plotted for the determination of the cut-off point at which the relevant studied variable achieves the best diagnostic performance. A Kaplan–Meier curve was plotted to calculate the cumulative survival time. Cox regression was carried out to determine the effect of several variables on the time (survival) taken for a specified event (death) to occur. Probability level (P value) was assumed to be significant if less than 0.05 and highly significant if the P value was less than 0.001. A P value was considered nonsignificant if greater than or equal to 0.05.


  Results Top


The results of this study are shown in [Table 1], [Table 2], [Table 3] and [Table 4] and [Figure 1], [Figure 2], [Figure 3] and [Figure 4]. Forty newly diagnosed patients with ALL were included in the present study. Twenty-three patients were pre-B ALL, one was pro-B ALL, four were B ALL, and 12 were T ALL. [Table 1] shows the clinical and hematological characteristics of the patients and the controls. The age of the patients ranged between 18 and 55 years, with (mean±SD) (32.5±10.8). Eighteen patients were men and 22 were women. There was a highly significant difference between the controls and the patients at presentation and after treatment in terms of the level of C/EBPα (P⩽0.001). [Table 2] shows that the number of patients after treatment was 33; 26 patients achieved hematological remission and seven were resistant (19 pro-B/pre-B ALL, 11 T ALL, and three B ALL). All patients had normal karyotyping, except one, who had multiple chromosomal abnormalities, and five patients were Ph+. [Table 3] and [Figure 1] show a significant difference between patients who achieved remission and resistant patients at diagnosis and at follow-up in terms of C/EBPα, whereas no significant difference was observed between patients who achieved remission and nonsurviving patients at diagnosis. There was no significant difference between high-risk and standard-risk patients in C/EBPα, except for Ph+ patients [Figure 2]. Using the receiver-operating characteristic curve [Figure 3], the area under the curve showed a cut-off value at (1) that best discriminated between patients with ALL at diagnosis and the control group with a sensitivity of 100.00%, a specificity of 64.00%, and a diagnostic accuracy of 86.15%. A Kaplan–Meir curve was plotted to calculate the cumulative survival time. Cox regression was carried out to examine the effect of several variables on the time (survival) taken for a specified event (death) to occur [Figure 4]. Variables included in the study were continuous variables (PB blast, BM blast, C/EBPα before, and C/EBPα after) and categorical variables (Ph chromosome, cell lineage, sex, age, total leucocytic count, and treatment). The variable that had the most influence on the survival time was C/EBPα (after treatment) [Table 4].
Figure 1: Comparison between controls and patients with complete remission, resistant patients, and patients who died both before and after treatment in terms of CCAATT/enhancer binding protein-α (C/EBPα).

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Figure 2: Comparison between controls, patients with Philadelphia (Ph)−, and patients with Ph+ and multiabnormalities both at diagnosis and at follow-up in terms of CCAATT/enhancer binding protein-α (C/EBPα).

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Figure 3: Receiver-operating characteristic curve for CCAATT/enhancer binding protein-α at diagnosis.

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Figure 4: Overall survival diagrams for CCAATT/enhancer binding protein-α.

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Table 1: Clinical and hematological data of the studied patients and controls at diagnosis and follow-up

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Table 2: Comparison between all patients at diagnosis and at follow-up in terms of BM examination

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Table 3: Comparison between patients who achieved remission versus resistant patients and patients who died in terms of C/EBPα before and after treatment

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Table 4: Cox regression analysis

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  Discussion Top


As C/EBPα is involved in all three hematopoietic checkpoints, cell proliferation, differentiation, and apoptosis, it is likely that impairment of either of these may induce leukemia. Therefore, inhibition of C/EBPα seems to be the epicenter of the pathophysiology of some leukemias 3. In the present study, C/EBPα was estimated by evaluating the level of expression of its candidate gene located on chromosome 19 by quantitative PCR.

The level of C/EBPα was evaluated in all patients at diagnosis and after receiving remission induction chemotherapy and was compared with its level in the healthy control samples [Table 1]. It was found that its level of expression in the control samples (3.79±4.39) was higher than its level of expression in patients with ALL both before and after treatment (0.17±0.18 and 0.32±0.32), respectively, with a statistically highly significant difference (P⩽0.001). These results are in agreement with those of Mercher and Gilliland 14, who reported that there are many lines of evidence indicating that loss of function of C/EBPA is leukemogenic, including dominant-negative mutations in C/EBPA itself and suppression of C/EBPA mRNA or C/EBPA protein expression by various leukemogenic fusion proteins.

The data of Akasaka et al. 15 indicated that deregulated expression of unmutated C/EBPα genes can occur in B-cell precursors (BCPs) and contribute toward malignant transformation. However, Chapiro et al. 11 found that overexpression of apparently normal C/EBPα RNA or protein was observed in six patients with (BCP-ALL) harboring the translocation t (14; 19)(q32; q13).

There was a statistically highly significant difference (P⩽0.001) between the level of C/EBPα in the control group (3.79±4.39) and its level in Ph− and Ph+ patients before treatment (0.19±0.18) and (0.02±0.03), respectively, as well as between Ph− and Ph+ patients. There was also a statistically significant difference (P⩽0.05) in its level after treatment between Ph− and Ph+ patients (0.37±0.33) and (0.05±0.05), respectively, being higher in the control group and Ph− patients [Figure 2].

Moreover, we found a statistically significant negative correlation between the Ph chromosome and the C/EPBα level in the studied patients at diagnosis and at follow-up (P<0.05) (rpb=−0.349 and −0.35), respectively. Our data were in agreement with those of Akasaka et al. 15, who reported that in hematologic malignancies with the translocation t (9;22)(q34;q11), BCR-ABL expression results in the downregulation of C/EBPα protein expression at the translational level, through upregulation of RNA-binding proteins.

In terms of the prognostic impact of C/EBPα, when we compared the level of C/EBPα in patients who achieved remission both before and after treatment (0.21±0.18) and (0.37±0.32), respectively, to its level in resistant patients before and after treatment (0.05±0.05) and (0.15±0.28), respectively, it was higher in the patients who achieved remission at presentation as well as after treatment, with a statistically significant difference (P⩽0.05) [Table 3], [Figure 2]. Analysis of these data indicated that C/EBPα was a good prognostic factor in our ALL studied patients. The final point relevant to the work of Fröhling et al. 16 was that although loss of C/EBPα activity is associated with a favorable prognosis in certain cytogenetic or molecular subgroups of AML, this might not be true for other types of leukemia. They reported that the expression of C/EBPα is also markedly reduced in the acute phase (myeloid blast crisis) of chronic myelogenous leukemia (CML-BC), which has a dismal prognosis.

To correlate C/EBPα to other prognostic factors in patients with ALL in the present study, we correlated the C/EBPα level before and after treatment to age, sex, total leucocytic count, hemoglobin, platelet count, LDH, uric acid, PB and BM blasts, extramedullary tumor volume, cerebrospinal fluid infiltration, and the Ph chromosome, but we did not find any statistically significant correlation, except with the Ph chromosome. Our results may be similar to the results obtained by Fos et al. 17, who concluded that suppressed C/EBPα DNA binding in patients with NK-AML was an independent marker for better overall survival and disease-free survival in a multivariable analysis that included FLT3-ITD, NPM1, and C/EBPα mutation status, white blood cell count, age, and LDH.

The overall survival for all studied patients with ALL was 13.511±1.520 months [Figure 4]. We examined the effect of several variables on the survival of the patients studied using Cox regression analysis. All risk factors were included in the regression analysis. The variable with the most influence on the survival time was C/EBPα (after treatment) [Table 4].

Analysis of these data indicates that C/EBPα has a good prognostic impact on the survival of the studied patients with ALL. This was supported by Fröhling et al. 16, who reported that on multivariate analysis, wild-type C/EBPα was an independent prognostic marker affecting the duration of remission.

From the previous discussion, we concluded that the transcription factor C/EBPα is a critical regulator of myeloid development 17. Although the role of C/EBPα in lymphoid cell fate decision may not be fully understood as yet, our data indicate that the deregulated expression of unmutated C/EBPα genes can occur in BCPs and contribute toward malignant transformation 15.

In conclusion, deficient C/EBPα transcription factor plays a role in lymphoid leukemogenesis. It is an independent prognostic factor in patients with ALL and it may have a major impact on their survival.[17]

 
  References Top

1.Graux C. Biology of acute lymphoblastic leukemia (ALL): clinical and therapeutic relevance. Transfus Apher Sci. 2011;44:183–189  Back to cited text no. 1
    
2.Litzow MR. Pharmacotherapeutic advances in the treatment of acute lymphoblastic leukaemia in adults. Drugs. 2011;71:415–442  Back to cited text no. 2
    
3.Trivedi AK, Pala P, Behreb G, Singhc SM. Multiple ways of C/EBPa inhibition in myeloid leukaemia. Eur J Cancer. 2008;44:1516–1523  Back to cited text no. 3
    
4.Randolph TR. Advances in acute lymphoblastic leukemia. Clin Lab Sci. 2004;17:235–245  Back to cited text no. 4
    
5.Hoffbrand AV, Moss PAH. Haemopoiesis. In: Essential haematology. 20086th ed. Oxford Wiley-Blackwell:1–14  Back to cited text no. 5
    
6.Schuster MB, Porse BT. CEBPα in leukemogenesis: identity and origin of the leukemia-initiating cell. Biofactors. 2009;35:227–231  Back to cited text no. 6
    
7.Fuchs O. Growth-inhibiting activity of transcription factor C/EBPα, its role in haematopoiesis and its tumour suppressor or oncogenic properties in leukaemias. Folia Biol (Praha). 2007;53:97–108  Back to cited text no. 7
    
8.Zaragoza K, Begay V, Schuetz A, Heinemann U, Leutz A. Repression of transcriptional activity of C/EBPα by E2F-dimerization partner complexes. Mol Cell Biol. 2010;30:2293–2304  Back to cited text no. 8
    
9.Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C. Epigenetic modulation of tumour suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst. 2006;98:396–406  Back to cited text no. 9
    
10.Leecharendkeat A, Tocharoentanaphol C, Auewarakul CU. CCAAT/enhancer binding protein-alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes. Int J Cancer. 2008;123:2321–2326  Back to cited text no. 10
    
11.Chapiro E, Russell L, Radford-Weiss I, Bastard C, Lessard M, Struski S, et al. Overexpression of CEBPA resulting from the translocation t(14; 19)(q32; q13) of human precursor-B-cell acute lymphoblastic leukaemia. Blood. 2006;108:3560–3563  Back to cited text no. 11
    
12.Pabst T, Mueller BU. Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin Cancer Res. 2009;15:5303–5307  Back to cited text no. 12
    
13.Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lympho-cytic leukemia. Cancer. 2004;101:2788–2801  Back to cited text no. 13
    
14.Mercher T, Gilliland DG. CEBPA dosage in leukemogenesis. Blood. 2006;108:3234  Back to cited text no. 14
    
15.Akasaka T, Balasas T, Russell LJ, Sugimoto K-J, Majid A, Walewska R, et al. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood. 2007;109:3451–3461  Back to cited text no. 15
    
16.Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22:624–633  Back to cited text no. 16
    
17.Fos J, Pabst T, Petkovic V, Ratschiller D, Mueller BU. Deficient CEBPA DNA binding function in normal karyotype AML patients is associated with favorable prognosis. Blood. 2011;117:4881–4884  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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