Title

Molecular signatures in childhood acute lymphoblastic leukemia in the kingdom of Saudi Arabia

Document Type

Article

Department

Biological and Biomedical Sciences; Haematology/Oncology

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood population. ALL is a heterogeneous group of disease that consists of various subtypes that allows to risk stratify the patients into favorable and unfavorable groups. Risk stratification of patients has definitely played an important role in the improvement of overall survival in childhood ALL. With the introduction of microarray technology, it has become increasingly clear that leukemia with different risk factors display distinct gene-expression profiles. The aim of this study was to investigate the gene expression profile on pediatric patients diagnosed with ALL using microarray analysis and study the common genetic subtypes in ALL samples using multiplex real-time RT-PCR. We studied 77 patients of newly diagnosed ALL at the King Faisal Specialist Hospital and Research center, Riyadh, Saudi Arabia. Using multiple parameters including age, sex and WBC count; we analyzed samples for differential expression of genes using the GeneChip® human genome U133 plus 2.0 microarray from Affymetrix. Based on the age of the patient, we compared samples between 1-9 years (favorable prognosis) to more than 10 years (unfavorable prognosis) of age. Using Avadis software from Strand genomics, we were able to identify 156 genes that were differentially expressed using a cutoff p value of 0.05. Out of this list, three genes were of interest to us as they were involved in either, cell cycle and/or apoptosis. They include the pro-apoptotic genes; TGF-beta induced apoptosis protein 2 (TAIP2) and Caspase Recruitment Domain member 14 (CARD14) that were 10.16 and 4.12 folds over-expressed in the favorable prognosis group respectively. In addition, another gene, cyclin A1 (CCNA1) that is involved in cell cycle was found to be down-regulated 4.84 folds in the favorable group. These genes have important clinical implications and can be used as prognostic markers in this age group. Interestingly, CyclinA1 is being currently targeted using siRNA to inhibit tumor growth and induce apoptosis in certain cancers. In addition to gene expression profiling, we also studied the four common genetic translocations detected in ALL by multiplex real-time RT-PCR. They include the t(12;21) TEL/AML1 fusion gene, t(9;22) BCR/ABL fusion gene, t(4;11) MLL1/AF4 fusion gene and t(1;19) E2A/PBX1 fusion gene. We found that the genetic translocation detected in our samples varied from the published data on western population. We detected 15% of TEL/AML1 translocation which was less than that found in the western population (22%), 4% of BCR/ABL that was higher than the western population (2.2%) and 6.5% of E2A/PBX1, that was higher than the western population (3.8%). These data have important clinical significance as they allow us to better understand the underlying biology of ALL as well as risk stratifies ALL patients according to their gene expression profiles and their genetic subtypes.

Comments

This work was published before the author joined Aga Khan University

Publication

Cancer Research

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