Expression Profile of Selected HOX Genes in Different Childhood ALL Subtypes

Abstract

Homeobox-containing (HOX) genes represent a large family of transcription factors that are involved in anteroposterior pattern formation during embryonic organogenesis. Besides their role in ontogenesis, various HOX genes have been associated with haematologic disorders including leukaemia. Multiple studies revealed that dysregulation of HOX genes is relevant to AML, ALL and CML; in addition, HOX genes are rearranged in some cases of human leukaemia and make part of fusion proteins such as NUP98-HOXA9, PBX1-E2A, etc. We have previously studied the pattern of HOX gene expression in chromosomally defined subsets of acute myeloid leukaemia and have shown that HOX genes exhibit a specific expression pattern throughout the AML subsets that can be related to the patient outcome. In this study, we studied the expression profile of various HOX genes in childhood acute lymphoblastic leukaemia (ALL) subtypes. We analysed mRNA levels of 23 different homeobox-containing genes in 59 children patients with ALL that were divided into six groups based on cytogenetic abnormalities and prednisone responsiveness: BCR/ABL, hyperdiploid ALL, TEL/AML1, MLL/AF4, T-ALL, prednisone good responders (PGR) and prednisone poor responders (PPR). Patient cDNA samples were analyzed using SYBRGreen I real-time quantitative PCR (qRT-PCR) and data obtained were normalized to the expression of ABL control gene. Our data indicate that certain HOX genes including HOXA3, HOXA4, HOXA5, HOXA6, HOXA9, HOXA10, HOXB2 or HOXB3 are differentially expressed throughout the ALL subtypes. Most notably, HOXA4, HOXA9, HOXB2 and HOXB3 mRNA levels appear to be elevated in T-ALL patients; hyperdiploid ALL patients display increased HOXA5 mRNA levels and HOXA3, HOXA6, HOXA9 and HOXA10 expression is higher in patients bearing the MLL/AF4 fusion gene. A relatively high level of HOXA5, HOXB2 and HOXB3 expression was observed in all patient groups. Furthermore, HOX gene expression distinguishes PGR from PPR group of patients; this divergence is most apparent in the case of HOXB2, HOXB3 and HOXB7. This study shows potential prognostic relevance of HOX gene levels in patients with childhood ALL. Data also confirm the differential HOX gene expression in various childhood ALL subtypes and underline the importance of certain HOX genes in leukemogenesis.