Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations

Abstract

Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)͞PBX1, IGH@͞MYC, ETV6(TEL)͞RUNX1(AML1), 11q23͞MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

“…We analysed MLL fusion proteins associated with an ALL disease phenotype. In a recent study comparing gene expression profiles of acute lymphoblastic leukemia patients, a HoxA7/HoxA10 signature was identified in MLL-rearranged ALL when compared with other B-lineage ALL or AML (Andersson et al, 2005;Supplementary Tables 21-23). Noteworthy, co-transfected cells lost this Hox signature, but showed an upregulation of the homeobox gene Nanog.…”

Epigenetics and the plasticity of differentiation in normal and cancer stem cells

“…Of the genes that are overexpressed in thyroid cancer (Jarzab et al, 2005), MAP17 is normally preferentially expressed in kidney and LAMB3 and SLC34A2 are normally preferentially expressed in lung. Of the genes expressed in leukemia but not in normal hematopoietic tissues (Andersson et al, 2005), GPRC5B, COBL, PLXNB1, TUSC3 and KIAA1644 are normally preferentially expressed in neuronal tissues (Table 2).…”

Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

“…18 Seventeen children (11 boys and 6 girls; median age 6 years, range 1-14 years) with ALLs harboring the t(12;21), as ascertained by reverse transcription polymerase chain reaction (RT-PCR) and/or FISH, were included in the study (Table 1); 14 samples were obtained at diagnosis and 3 (nos. 3, 6 and 12) at relapse.…”