Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice

Kiyoko Yamamoto; Shinobu Tsuzuki; Yosuke Minami; Yukiya Yamamoto; Akihiro Abe; Koichi Ohshima; Masao Seto; Tomoki Naoe

doi:10.1371/journal.pone.0074864

Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice

PLoS One. 2013 Sep 30;8(9):e74864. doi: 10.1371/journal.pone.0074864. eCollection 2013.

Authors

Kiyoko Yamamoto¹, Shinobu Tsuzuki, Yosuke Minami, Yukiya Yamamoto, Akihiro Abe, Koichi Ohshima, Masao Seto, Tomoki Naoe

Affiliation

¹ Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan ; Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Abstract

Patients in the chronic phase (CP) of chronic myelogenous leukemia (CML) have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC) phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt.) AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blast Crisis / metabolism*
Blast Crisis / pathology
Blotting, Western
Core Binding Factor Alpha 2 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / metabolism*
DNA Mutational Analysis
DNA Primers / genetics
Flow Cytometry
Fusion Proteins, bcr-abl / metabolism*
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Mice
Mice, Inbred C57BL
Mutation, Missense / genetics
Phenotype*
Plasmids / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction

Substances

Core Binding Factor Alpha 2 Subunit
DNA Primers
RNA, Small Interfering
Runx1 protein, mouse
Fusion Proteins, bcr-abl

Grants and funding

This work was supported by the Health and Labor Scientific Research Grant for Clinical Cancer Research (H23-Gan Rinsho-Ippan-004), Grant-in-Aid for Reseach from the Ministry of Health, Labor and Welfare (23-A-23), grant-in-aid for scientific research from The Ministry of Education, Culture, Sports, Science and Technology (M.S.), a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (S.T.), and a research grant from the Princess Takamatsu Cancer Research Fund (11-24307) (S.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.