title: PBX3 is an important cofactor of HOXA9 in leukemogenesis.
abstract: Although PBX proteins are known to increase DNA-binding/transcriptional activity of HOX proteins through their direct binding, the functional importance of their interaction in leukemogenesis is unclear.We recently reported that overexpression of a 4-homeobox-gene signature (ie, PBX3/HOXA7/HOXA9/HOXA11) is an independent predictor of poor survival in patients with cytogenetically abnormal acute myeloid leukemia (CA-AML). Here we show that it is PBX3, but not PBX1 or PBX2, that is consistently coexpressed with HOXA9 in various subtypes of CA-AML, particularly MLL-rearranged AML, and thus appears as a potential pathologic cofactor of HOXA9 in CA-AML. We then show that depletion of endogenous Pbx3 expression by shRNA significantly inhibits MLL-fusion-mediated cell transformation, and coexpressed PBX3 exhibits a significantly synergistic effect with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo. Furthermore, as a proof of concept, we show that a small peptide, namely HXR9, which was developed to specifically disrupt the interactions between HOX and PBX proteins, can selectively kill leukemic cells with overexpression of HOXA/PBX3 genes. Collectively, our data suggest that PBX3 is a critical cofactor of HOXA9 in leukemogenesis, and targeting their interaction is a feasible strategy to treat presently therapy resistant CA-AML (eg, MLL-rearranged leukemia) in which HOXA/PBX3 genes are overexpressed.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. zjli@uchicago.edu
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Gia-Ming
authors.initials: GM
authors.lastname: Hong
authors.forename: Rejani B
authors.initials: RB
authors.lastname: Kunjamma
authors.forename: Haomin
authors.initials: H
authors.lastname: Ren
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.forename: Chong-Zhi
authors.initials: CZ
authors.lastname: Wang
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Morgan
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Chun-Su
authors.initials: CS
authors.lastname: Yuan
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology*; D015321:Gene Rearrangement / Q000235:genetics; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C522972:HXR9 peptide; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C090465:PBX2 protein, human; C481797:Pbx1 protein, mouse; C490382:Pbx2 protein, mouse; D010455:Peptides; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C083400:PBX1 protein, human; C090466:proto-oncogene protein Pbx3; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase