Early treatment sensitivity in childhood acute lymphoblastic leukemia is associated with gain of chromosome 21.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5271 Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. In vivo response to initial therapy, as assessed by determination of minimal residual disease at 5 and 12 weeks of treatment, has evolved as the strongest prognostic factor in pediatric ALL patients treated according to the BFM regime. In this study, ten patients with a poor treatment response (MRD load > 10-3 at week 12, MRD-high risk, HR), five treatment-sensitive patients (no measurable MRD at weeks 5 and 12, MRD-standard risk, SR) and three patient with an intermediate treatment sensitivity (any MRD positivity at week 5, MRD load < 10-3 at week 12, MRD intermediate risk, IR) were investigated by means of high-resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridization (array-CGH). To ensure homogeneity with regard to prognostic factors, the following inclusion criteria were used: B cell precursor or common ALL, DNA index of 1.0, no BCR/ABL, no MLL/AF4, no TEL/AML1 rearrangements. A gain for all chromosome 21-related BAC clones was observed in all five SR as well as in two out of three IR risk patients. None of the ten HR patients showed a gain of any region of chromosome 21. This result could be confirmed by means of fluorescence in situ hybridization using the LSI AML1/ETO DC probe set. Interestingly, the one MRD-IR patient demonstrating no gain of chromosome 21 relapsed 29 months after diagnosis. Recurrent genomic alterations in the group of HR patients were loss of chromosomal region 2p11.22 (9/10), a gain of 8q24.13 (7/10) and loss of 14q32 (8/10). To exclude that these alterations may be genomic polymorphisms we additionally profiled the DNA prepared from the patients at remission stage. No genomic alterations were observed in this material. Besides the basic level of chromosome 21 gain, higher levels of gain or amplification observed for individual regions were found in 4 SR/IR patients. The further characterization of these amplified sequences is under way and may lead to the identification of therapy-related target genes.