title: Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1.
abstract: Nucleophosmin 1 (NPM1) is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal, which causes NPM1c+ to be localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1 induced p53 and p21, decreased the percentage of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and unmutated NPM1. Notably, knockdown of NPM1 by shRNA abolished lethal AML phenotype induced by OCI-AML3 cells in NOD/SCID mice. Knockdown of NPM1 also sensitized OCI-AML3 to all-trans retinoic acid (ATRA) and cytarabine. Inhibition of NPM1 oligomerization by NSC348884 induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+ to ATRA. This effect was significantly less in AML cells coexpressing FLT3-ITD, or in AML or normal CD34+ progenitor cells expressing wild-type NPM1. Thus, attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes NPM1c+ expressing AML cells to treatment with ATRA and cytarabine.
authors: The University of Kansas Medical Center, KS City, KS, USA.
authors: Ramesh
authors: R
authors: Balusu
authors: Warren
authors: W
authors: Fiskus
authors: Rekha
authors: R
authors: Rao
authors: Daniel G
authors: DG
authors: Chong
authors: Srilatha
authors: S
authors: Nalluri
authors: Uma
authors: U
authors: Mudunuru
authors: Hongwei
authors: H
authors: Ma
authors: Lei
authors: L
authors: Chen
authors: Sreedhar
authors: S
authors: Venkannagari
authors: Kyungsoo
authors: K
authors: Ha
authors: Sunil
authors: S
authors: Abhyankar
authors: Casey
authors: C
authors: Williams
authors: Joseph
authors: J
authors: McGuirk
authors: Hanna Jean
authors: HJ
authors: Khoury
authors: Celalettin
authors: C
authors: Ustun
authors: Kapil N
authors: KN
authors: Bhalla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050505:Mutant Proteins / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000090243:Nucleophosmin; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000090243:Nucleophosmin