Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations.
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), 11q23/MLL, 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.
Andersson
Anna
A
Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden. anna.andersson@med.lu.se
Olofsson
Tor
T
Lindgren
David
D
Nilsson
Björn
B
Ritz
Cecilia
C
Edén
Patrik
P
Lassen
Carin
C
Råde
Johan
J
Fontes
Magnus
M
Mörse
Helena
H
Heldrup
Jesper
J
Behrendtz
Mikael
M
Mitelman
Felix
F
Höglund
Mattias
M
Johansson
Bertil
B
Fioretos
Thoas
T
D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D019070:Cell Lineage; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006413:Hematopoietic System / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein; D020411:Oligonucleotide Array Sequence Analysis; D011003:Ploidies; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D025341:Principal Component Analysis; D014157:Transcription Factors / Q000737:chemistry
D018076:DNA, Complementary; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein