title: EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs.
abstract: The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that ∼ 43% of all mixed lineage leukemia (MLL)-rearranged leukemias are EVI1(pos). High EVI1 expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELL fusion genes. In addition, we present evidence that EVI1(pos) MLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1(neg) MLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1 expression on transformation of Evi1(pos) HSCs. MLL-AF9 does not activate Evi1 expression in MLL-AF9-transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1(neg). Moreover, shRNA-mediated knockdown of Evi1 in an Evi1(pos) MLL-AF9 mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1 provides a growth-promoting signal. Using the Evi1(pos) MLL-AF9 mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1 expression. We conclude that EVI1 is a critical player in tumor growth in a subset of MLL-rearranged AMLs.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Eric M J
authors.initials: EM
authors.lastname: Bindels
authors.forename: Marije
authors.initials: M
authors.lastname: Havermans
authors.forename: Sanne
authors.initials: S
authors.lastname: Lugthart
authors.forename: Claudia
authors.initials: C
authors.lastname: Erpelinck
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wocjtowicz
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.forename: Elwin
authors.initials: E
authors.lastname: Rombouts
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: Erdogan
authors.initials: E
authors.lastname: Taskesen
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Haanstra
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Hudson
authors.forename: John H
authors.initials: JH
authors.lastname: Kersey
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification* / Q000209:etiology / Q000235:genetics*; D008239:Lysine / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C000715470:MAS1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C474558:MLL-AF9 fusion protein, human; C499305:Mecom protein, mouse; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D008239:Lysine