Characterization of CEBPA Mutations and Polymorphisms and their Prognostic Relevance in De Novo Acute Myeloid Leukemia Patients.

Santhi Sarojam,Geetha Narayanan,Sangeetha Vijay,Jayadevan Sreedharan,Sureshkumar Raveendran,Hariharan Sreedharan

doi:10.7314/apjcp.2015.16.9.3785

Abstract

The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcriptional factor that plays a crucial role in the control of proliferation and differentiation of myeloid precursors. This gene was recognized as the target of genetic alterations and were associated with clinical complexity among AML. We here analyze the frequency and types of CEBPA mutations and polymorphisms in a de novo AML patients from South India and tried to find out associations of these variations with different clinical parameters and the prognostic significance in AML. Study was carried out in 248 de novo AML patients, cytogenetic analysis was performed from the bone marrow samples and was karyotyped. PCR-SSCP analysis and sequencing was performed for the detection of CEBPA gene variations. All the statistical analysis was performed using SPSS 17 (statistical package for social sciences) software. Pearson Chi-square test, Mann-Whitney U test, Kaplan-Meier survival analysis and log rank tests were performed. CEBPA mutations were detected in 18% and CEBPA polymorphisms were detected in 18.9% of AML cases studied. Most of the mutations occured at the C terminal region. Polymorphisms were detected in both N and C terminal region. with most common being, c.584_589dup ACCCGC and c.690G>T. A significant association was not observed for the mutation and polymorphism with respect to clinical and laboratory parameters. Survival advantage was observed for the mutated cases compared to non mutated cases, especially for the normal karyotype groups. Polymorphisms has no effect on the survival pattern of AML patients. CEBPA mutation and polymorphisms were observed with similar frequency and was identified in all the FAB subtypes as well as in cytogenetic risk groups in our study population, but CEBPA mutations alone confer a prognostic value for NK AML patients.

Highlights

Gene mutations and aberrant chromosomal translocations provide a selective growth advantage to the leukemic stem cells (Frohling et al, 2005)
CCAAT/enhancer-binding protein-alpha (CEBPA) mutations were detected in 18% and CEBPA polymorphisms were detected in 18.9% of AML cases studied
CEBPA mutation and polymorphisms were observed with similar frequency and was identified in all the FAB subtypes as well as in cytogenetic risk groups in our study population, but CEBPA mutations alone confer a prognostic value for NK AML patients

Summary

Introduction

Gene mutations and aberrant chromosomal translocations provide a selective growth advantage to the leukemic stem cells (Frohling et al, 2005). Among the oncogenes that affects proliferation and cell death, the most important is those that are involved in the haematopoietic differentiation pathways (Tenen, 2003). CEBPA gene, a single exon gene located on chromosome 19q13.1 coding for 358 aminoacids, forming a 42-KDa protein belongs to the CCAAT/enhancer binding protein family, which is involved in the balance between cell proliferation and terminal differentiation (Leroy et al, 2005). CEBPA play a crucial role in granulocytic differentiation and could block the progression from the G1 to S phase by inducing the terminal differentiation of haematopoietic cells (Friedman et al, 2002; Cammenga et al, 2003). Deregulation of CEBPA activity is widely known to contribute to the myeloid transformation via reducing the differentiation potential

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