The proposed study will assess molecular genetic markers in pediatric acute lymphoblastic leukemia (ALL) by quantitation of DNA and RNA using real-time PCR detection, measured on an ABI PRISM 7700 instrument. The two aims are, firstly, to examine the prognostic significance of deletion of the p15, p16 and p19ARF genes for a cohort of 300 pediatric patients treated on three CCG (Children's Cancer Group) protocols (CCG-1882, CCG-1901 and CCG-1922) that are based on Berlin-Frankfurt-Muenster (BFM) therapy. This investigation is designed to confirm and extend our recently published findings on the prognostic significance of p16 deletion in childhood ALL (Kees et al., 1997) in a large cohort of children treated uniformly in multi-institution clinical trials. Secondly, to test the hypothesis that the incidence of specific nonrandom combinations of these molecular genetic lesions is correlated with clinical outcome. Although the concept of multiple hit genetic defects is accepted, there is as yet no published report on the frequency of these combinations occurring in pediatric ALL. The study will be conducted using cryopreserved specimens. Since patients to be studied have a follow-up time of between four and eight years from diagnosis, this study will provide correlative information on molecular genetic prognostic factors present in the leukemic cells of these patients and event-free survival (EFS). The study will provide definitive data on the relationship of these molecular lesions in pediatric patients treated on BFM-based protocols. Translational research like this one will further define prognostic biological characteristics and will assist in gaining a better understanding of clinical outcome for pediatric ALL subgroups. It will provide the basis for further stratification of pediatric ALL as determined by molecular genetic profile of the leukemic cells of patients who may benefit from different treatment approaches. The ultimate aim of this project is to permit a reduction of therapy for cohorts of patients whose molecular genetic profile would suggest excellent prospect of cure using current therapies, while identifying other subgroups that may need more intensive or novel treatment. The study will be performed making use of the most advanced technology for quantitative PCR measurement of multiple genes. Such precise information could not be obtained using older methodology like Southern blotting.
| Gottardo, N G; Jacoby, P A; Sather, H N et al. (2005) Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols. Leukemia 19:1705-8 |
| Carter, Tina L; Terry, Philippa; Gottardo, Nicholas et al. (2004) Deletion of one copy of the p16INK4A tumor suppressor gene is implicated as a predisposing factor in pediatric leukemia. Biochem Biophys Res Commun 318:852-5 |
| Kees, U R; Heerema, N A; Kumar, R et al. (2003) Expression of HOX11 in childhood T-lineage acute lymphoblastic leukaemia can occur in the absence of cytogenetic aberration at 10q24: a study from the Children's Cancer Group (CCG). Leukemia 17:887-93 |
| Carter, T L; Reaman, G H; Kees, U R (2001) INK4A/ARF deletions are acquired at relapse in childhood acute lymphoblastic leukaemia: a paired study on 25 patients using real-time polymerase chain reaction. Br J Haematol 113:323-8 |
