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PMID: 9144232 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Acute leukemia with promyelocytic features in PML/RARalpha transgenic mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 10 ·1997-05-13 ·Pages 5302-7

He LZ, Tribioli C, Rivi R, Peruzzi D, Pelicci PG, Soares V, Cattoretti G, Pandolfi PP

Abstract

Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) locus on chromosome 17. In the majority of cases, RARalpha translocates and fuses with the promyelocytic leukemia (PML) gene located on chromosome 15. The resulting fusion genes encode the two structurally unique PML/RARalpha and RARalpha/PML fusion proteins as well as aberrant PML gene products, the respective pathogenetic roles of which have not been elucidated. We have generated transgenic mice in which the PML/RARalpha fusion protein is specifically expressed in the myeloid-promyelocytic lineage. During their first year of life, all the PML/RARalpha transgenic mice have an abnormal hematopoiesis that can best be described as a myeloproliferative disorder. Between 12 and 14 months of age, 10% of them develop a form of acute leukemia with a differentiation block at the promyelocytic stage that closely mimics human APL even in its response to retinoic acid. Our results are conclusive in vivo evidence that PML/RARalpha plays a crucial role in the pathogenesis of APL.

MeSH Terms
Aging Animals Blood Cell Count Bone Marrow/pathology Cell Differentiation/drug effects Chromosomes, Human, Pair 17 DNA Primers Hematopoiesis Hematopoietic Stem Cells/cytology,drug effects,pathology Humans Leukemia, Promyelocytic, Acute/blood,genetics,pathology Lymphocytes/cytology,drug effects,pathology Mice Mice, Transgenic Myeloproliferative Disorders/genetics,physiopathology Neoplasm Proteins Nuclear Proteins Polymerase Chain Reaction Promyelocytic Leukemia Protein Receptors, Retinoic Acid/biosynthesis,genetics Recombinant Fusion Proteins/biosynthesis Reference Values Retinoic Acid Receptor alpha Spleen/pathology Transcription Factors/biosynthesis,genetics Translocation, Genetic Tretinoin/pharmacology Tumor Suppressor Proteins
Chemicals
DNA Primers Neoplasm Proteins Nuclear Proteins Pml protein, mouse Promyelocytic Leukemia Protein RARA protein, human Rara protein, mouse Receptors, Retinoic Acid Recombinant Fusion Proteins Retinoic Acid Receptor alpha Transcription Factors Tumor Suppressor Proteins PML protein, human Tretinoin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
He L Z
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, Molecular Biology and Cell Biology Programs, Sloan-Kettering Institute, 1275 York Avenue, New York, NY, 10021, USA.
Tribioli C
Rivi R
Peruzzi D
Pelicci P G
Soares V
Cattoretti G
Pandolfi P P
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.94.10.5302
Published
1997-05-13
Pages
5302-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24673
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.94.10.5302 PMC Full Text View journal details
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