TY - JOUR
T1 - PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias
AU - Ronchini, Chiara
AU - Brozzi, Alessandro
AU - Riva, L.
AU - Luzi, L
AU - Gruszka, A M
AU - Melloni, Giorgio E M
AU - Scanziani, Eugenio
AU - Dharmalingam, G
AU - Mutarelli, Margherita
AU - Belcastro, Vincenzo
AU - Lavorgna, S
AU - Rossi, V
AU - Spinelli, O.
AU - Biondi, A.
AU - Rambaldi, Alessandro
AU - Lo-Coco, F
AU - Di Bernardo, Diego
AU - Pelicci, P G
PY - 2016/12/27
Y1 - 2016/12/27
N2 - It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.Leukemia advance online publication, 20 January 2017; doi:10.1038/leu.2016.386.
AB - It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.Leukemia advance online publication, 20 January 2017; doi:10.1038/leu.2016.386.
KW - Journal Article
U2 - 10.1038/leu.2016.386
DO - 10.1038/leu.2016.386
M3 - Article
C2 - 28025581
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -