title: Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid.
abstract: Enhanced expression of ecotropic viral integration site 1 (EVI-1) occurs in ∼10% of acute myeloid leukemia (AML) patients and is associated with a very poor disease outcome. Patients with EVI-1-positive AML have poor initial responses to chemotherapy and high relapse rates, indicating an urgent need for alternative treatment strategies improving clinical outcome for these patients. Because treatment of acute promyelocytic patients with all-trans retinoic acid (ATRA) has improved the survival of these patients substantially, we investigated whether ATRA might also be effective for the subgroup of AML patients with EVI-1 overexpression. Here, we show that a substantial part of the EVI-1-positive AML cases respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts. Most importantly, we demonstrate that in vivo treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Altogether, our results show that a considerable part of the EVI-1-positive primary AML cases are sensitive to ATRA, suggesting that combining ATRA with the currently used conventional chemotherapy might be a promising treatment strategy decreasing relapse rates and enhancing complete remissions in this poor prognostic subgroup of AML patients.
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Han J M P
authors.initials: HJ
authors.lastname: Verhagen
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Marjon A
authors.initials: MA
authors.lastname: Smit
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Arjo
authors.initials: A
authors.lastname: Rutten
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Fedor
authors.initials: F
authors.lastname: Denkers
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pino J
authors.initials: PJ
authors.lastname: Poddighe
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: Merle
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.affiliation: Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Linda
authors.initials: L
authors.lastname: Smit
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D016513:Mice, SCID; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D014212:Tretinoin