Format

Send to

Choose Destination
Exp Hematol. 2018 Aug;64:71-83.e8. doi: 10.1016/j.exphem.2018.04.007. Epub 2018 May 5.

Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML).

Author information

1
INSERM U935, F94807 Villejuif, France; Université Paris Sud, F94270 Le Kremlin-Bicêtre, France.
2
INSERM, U935, F86000 Poitiers, France; Centre Hospitalier de la Roche-sur-Yon, Service de Médecine Onco-Hématologie, la Roche-sur-Yon, F85925 France.
3
INSERM, U935, F86000 Poitiers, France.
4
INSERM, U935, F86000 Poitiers, France; Centre Hospitalier Universitaire de Poitiers, Service de Cancérologie Biologique, F86000 Poitiers, France.
5
INSERM U935, F94807 Villejuif, France.
6
Centre Hospitalier Universitaire de Poitiers, Service de Cancérologie Biologique, F86000 Poitiers, France.
7
INSERM U935, F94807 Villejuif, France; Université Paris Sud, F94270 Le Kremlin-Bicêtre, France; Hôpital Paul Brousse, Service d'Hématologie Biologique, F94800 Villejuif, France.
8
INSERM, CIC-P 1402, F86000 Poitiers, France; Centre Hospitalier Universitaire de Poitiers, Service d'Oncologie Hématologique et Thérapie Cellulaire, F86000, Poitiers, France.
9
INSERM U935, F94807 Villejuif, France; Université Paris Sud, F94270 Le Kremlin-Bicêtre, France; Hôpital Paul Brousse, Service d'Hématologie Biologique, F94800 Villejuif, France; Hôpital Bicêtre, Service d'Hématologie Biologique, F94270 Le Kremlin Bicêtre, France. Electronic address: turviv33@gmail.com.

Abstract

The BCR-ABL oncogene, the hallmark of chronic myeloid leukemia (CML), has been shown to activate several signaling pathways in leukemic cells. The natural history of this disease has been radically modified by tyrosine kinase inhibitors (TKIs). However, resistance to several lines of TKI therapies and progression to blast crisis (BC) remain significant concerns. To identify novel signaling pathways induced by BCR-ABL, we performed a transcriptome analysis in a BCR-ABL-expressing UT-7 cell line. More than 2000 genes differentially expressed between BCR-ABL-expressing and parental UT-7 cells were identified and ETS1 was found to be the most upregulated. ETS1 protein expression was also shown to be highly increased in UT-7 cells expressing BCR-ABL either constitutively or under the control of TET-inducible promoters. ETS1 expression is tyrosine-kinase dependent because it was reduced by TKIs. A significant increase of ETS1 messenger RNA (mRNA) expression was observed in blood cells from CML patients at diagnosis compared with healthy controls. Integration of publicly available chromatin immunoprecipitation sequencing and transcriptomic data with our results allowed us to identify potential ETS1 targets, some of which are involved in the progression of CML. The messenger RNA expression of two of these genes (DNM3 and LIMS1) was found to be associated with the absence of major cytogenetic response after 1 year of imatinib therapy. The present work demonstrates for the first time the involvement of the ETS1 transcriptional program in the experimental UT-7 model and a large cohort of CML patients.

PMID:
29733872
DOI:
10.1016/j.exphem.2018.04.007
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center