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The outcome of children and adults with acute lymphoblastic leukemia is markedly different. Since there is limited information on the distribution of clinico-biological variables in different age cohorts, we analyzed 5202 patients with acute lymphoblastic leukemia enrolled in the Italian multicenter AIEOP and GIMEMA protocols and stratified them in nine age cohorts. The highest prevalence of acute lymphoblastic leukemia was observed in children, although a second peak was recorded from the 4(th) decade onwards. Interestingly, the lowest incidence was found in females between 14-40 years. Immunophenotypic characterization showed a B-lineage in 85.8% of patients: a pro-B stage, associated with MLL/AF4 positivity, was more frequent in patients between 10-50 years. T-lineage leukemia (14.2%) was rare among small children and increased in patients aged 10-40 years. The prevalence of the BCR/ABL1 rearrangement increased progressively with age starting from the cohort of patients 10-14 years old and was present in 52.7% of cases in the 6th decade. Similarly, the MLL/AF4 rearrangement constantly increased up to the 5(th) decade, while the ETV6/RUNX1 rearrangement disappeared from the age of 30 onwards. This study shows that acute lymphoblastic leukemia in adolescents and young adults is characterized by a male prevalence, higher percentage of T-lineage cases, an increase of poor prognostic molecular markers with aging compared to cases in children, and conclusively quantified the progressive increase of BCR/ABL(+) cases with age, which are potentially manageable by targeted therapies.

Background and Objectives: A common non-random translocation in childhood pre-B acute lymphoblastic leukemia (ALL) is t(1;19)(q23;p13), usually resulting in the expression of the chimeric gene E2A-PBX1. The role of this fusion gene during leukemogenesis is not yet fully understood; one approach to investigate its function is to selectively deplete the E2A-PBX1 protein and examine the consequences., Design and Methods: We tested the efficacy of anti-E2A-PBX1 siRNA in the 697 pre-B leukemia cell line. Transfection was monitored by fluorescence microscopy and FACS, while E2A-PBX1 mRNA expression was measured using real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The reduction of the level of the corresponding fusion protein was assessed by western blot analysis and the expression of putative downstream target genes was detected by SYBR Green PCR., Results: We demonstrated efficient downregulation induced by anti-E2A-PBX1 siRNA in 697 t(1;19)-positive leukemia cells. In particular, E2A-PBX1 silencing affected the EB-1 gene, which encodes for a protein that could contribute to the transformed phenotype of pre-B ALL. The detected EB-1 expression was reduced to 25% of the normal expression level in non-transfected 697 cells. Furthermore, the significant decrease in Wnt16b mRNA levels (but not of the Wnt16a isoform of the Wnt16 gene), observed following depletion of the fusion gene, confirms the hypothesis that Wnt16b is a target of E2A-PBX1. The siRNA inhibition was followed by an increase in apoptosis and similar results were obtained in two other ALL cell lines, one with and one without the t(1;19) translocation., Interpretation and Conclusions: Targeted-E2A-PBX1 inhibition leads to reduced expression of the EB-1 and Wnt16b genes; aberrant expression of these genes may be a key step in leukemogenesis in t(1;19)-positive pre-B leukemia.

Background and Objectives: Microarray gene expression profiling has been widely applied to characterize hematologic malignancies, has attributed a molecular signature to leukemia subclasses and has allowed new subclasses to be distinguished. We set out to use microarray technology to identify novel genes relevant for leukemogenesis. To this end we used a unique leukemia-enriched cDNA microarray platform., Design and Methods: The systematic sequencing of cDNA libraries of normal and leukemic bone marrow allowed us to increase the number of genes to yield a new release of a previously generated cDNA microarray. Using this platform we analyzed the expression profiles of 4,670 genes in bone marrow samples from 18 pediatric patients with acute lymphoblastic leukemia (ALL)., Results: Expression profiling consistently distinguished the leukemia patients into three groups, those with T-ALL, B-ALL and B-ALL with MLL/AF4 rearrangement, in agreement with the clinical classification. Our platform identified 30 genes that best discriminate these three subtypes. Using mini-array technology these 30 genes were validated in another cohort of 17 patients. In particular we identified two novel genes not previously reported: endomucin (EMCN) and ubiquitin specific protease 33 (USP33) that appear to be over-expressed in B-ALL relative to their expression in T-ALL., Interpretation and Conclusions: Microarray technology not only allows the distinction between disease subclasses but also offers a chance to identify new genes involved in leukemogenesis. Our approach of using a unique platform has proven to be fruitful in identifying new genes and we suggest exploration of other malignancies using this approach.