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PMID: 24184354 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease.

Experimental hematology ·Vol. 42 ·No. 2 ·2014-02-00 ·Pages 101-13.e5

Rau R, Magoon D, Greenblatt S, Li L, Annesley C, Duffield AS, Huso D, McIntyre E, Clohessy JG, Reschke M, Pandolfi PP, Small D, Brown P

Abstract

Cytoplasmic nucleophosmin (NPMc(+)) mutations and FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations are two of the most common known molecular alterations in acute myeloid leukemia (AML); they frequently occur together, suggesting cooperative leukemogenesis. To explore the specific relationship between NPMc+ and FLT3/ITD in vivo, we crossed Flt3/ITD knock-in mice with transgenic NPMc+ mice. Mice with both mutations develop a transplantable leukemia of either myeloid or lymphoid lineage, definitively demonstrating cooperation between Flt3/ITD and NPMc+. In mice with myeloid leukemia, functionally significant loss of heterozygosity of the wild-type Flt3 allele is common, similar to what is observed in human FLT3/ITD+ AML, providing further in vivo evidence of the importance of loss of wild-type FLT3 in leukemic initiation and progression. Additionally, in vitro clonogenic assays reveal that the combination of Flt3/ITD and NPMc+ mutations causes a profound monocytic expansion, in excess of that seen with either mutation alone consistent with the predominance of myelomonocytic phenotype in human FLT3/ITD+/NPMc+ AML. This in vivo model of Flt3/ITD+/NPMc+ leukemia closely recapitulates human disease and will therefore serve as a tool for the investigation of the biology of this common disease entity.

MeSH Terms
Alleles Animals Cytoplasm/metabolism Gene Duplication Leukemia, Myeloid, Acute/genetics Loss of Heterozygosity Mice Mice, Transgenic Mutation Nuclear Proteins/genetics,metabolism Nucleophosmin Reverse Transcriptase Polymerase Chain Reaction fms-Like Tyrosine Kinase 3/genetics
Chemicals
NPM1 protein, human Nuclear Proteins Nucleophosmin Flt3 protein, mouse fms-Like Tyrosine Kinase 3
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Rau Rachel
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: [email protected].
Magoon Daniel
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Greenblatt Sarah
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Li Li
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Annesley Colleen
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Duffield Amy S
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Huso David
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
McIntyre Emily
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Clohessy John G
Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Reschke Markus
Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Pandolfi Pier Paolo
Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Small Donald
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Brown Patrick
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Article Info
Journal
Experimental hematology
Abbr.
Exp Hematol
ISSN
1873-2399
DOI
10.1016/j.exphem.2013.10.005
Email
[email protected]
Published
2014-02-00
Epub
2013-00-29
Pages
101-13.e5
Language
English
Region
Netherlands
NLM ID
0402313
PMCID
PMC3932758
Subset
IM
Grants
NCI NIH HHS · R01 CA090668 · United States
NCI NIH HHS · K23CA111728 · United States
NCI NIH HHS · P01CA70970 · United States
NCI NIH HHS · P01 CA070970 · United States
NCI NIH HHS · T32 CA060441 · United States
NCI NIH HHS · K23 CA111728 · United States
NCI NIH HHS · R01CA90668 · United States
External Links
PubMed source DOI: 10.1016/j.exphem.2013.10.005 PMC Full Text View journal details
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