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PMID: 21719597 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1.

Blood ·Vol. 118 ·No. 11 ·2011-09-15 ·Pages 3096-106

Balusu R, Fiskus W, Rao R, Chong DG, Nalluri S, Mudunuru U, Ma H, Chen L, Venkannagari S, Ha K, Abhyankar S, Williams C, McGuirk J, Khoury HJ, Ustun C, Bhalla KN

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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Cell Differentiation/drug effects Cell Survival/drug effects Cells, Cultured Drug Synergism Female Gene Expression Regulation, Leukemic/drug effects HL-60 Cells Humans Leukemia, Myeloid, Acute/metabolism Mice Mice, Inbred NOD Mice, SCID Mutant Proteins/metabolism,physiology Nuclear Proteins/antagonists & inhibitors,genetics,metabolism,physiology Nucleophosmin Protein Multimerization/drug effects,physiology RNA, Small Interfering/pharmacology U937 Cells Up-Regulation/drug effects Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents Mutant Proteins NPM1 protein, human Npm1 protein, mouse Nuclear Proteins RNA, Small Interfering Nucleophosmin
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Balusu Ramesh
The University of Kansas Medical Center, KS City, KS, USA.
Fiskus Warren
Rao Rekha
Chong Daniel G
Nalluri Srilatha
Mudunuru Uma
Ma Hongwei
Chen Lei
Venkannagari Sreedhar
Ha Kyungsoo
Abhyankar Sunil
Williams Casey
McGuirk Joseph
Khoury Hanna Jean
Ustun Celalettin
Bhalla Kapil N
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2010-09-309674
Published
2011-09-15
Epub
2011-00-30
Pages
3096-106
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC6710561
Subset
IM
Grants
NCI NIH HHS · R01 CA171338 · United States
NCI NIH HHS · R01 CA173877 · United States
Corrections
CommentIn
PMID: 21921055
External Links
PubMed source DOI: 10.1182/blood-2010-09-309674 PMC Full Text View journal details
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