TY - JOUR
T1 - Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling
AU - Bourquin, Jean Pierre
AU - Subramanian, Aravind
AU - Langebrake, Claudia
AU - Reinhardt, Dirk
AU - Bernard, Olivier
AU - Ballerini, Paola
AU - Baruchel, André
AU - Cavé, Hélène
AU - Dastugue, Nicole
AU - Hasle, Henrik
AU - Kaspers, Gertjan L.
AU - Lessard, Michel
AU - Michaux, Lucienne
AU - Vyas, Paresh
AU - Van Wering, Elisabeth
AU - Zwaan, Christian M.
AU - Golub, Todd R.
AU - Orkin, Stuart H.
PY - 2006/2/28
Y1 - 2006/2/28
N2 - Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
AB - Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
KW - Down syndrome
KW - GATA1
UR - http://www.scopus.com/inward/record.url?scp=33644759290&partnerID=8YFLogxK
U2 - 10.1073/pnas.0511150103
DO - 10.1073/pnas.0511150103
M3 - Article
C2 - 16492768
AN - SCOPUS:33644759290
SN - 0027-8424
VL - 103
SP - 3339
EP - 3344
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -