Upregulation of c-myc gene accompanied by PU.1 deficiency in radiation-induced acute myeloid leukemia in mice.
OBJECTIVE
High-dose radiation exposure induces acute myeloid leukemia (AML) in C3H mice, most of which have a frequent hemizygous deletion around the D2Mit15 marker on chromosome 2. This region includes PU.1, a critical candidate gene for initiation of leukemogenesis. To identify novel cooperative genes with PU.1, relevant to radiation-induced leukemogenesis, we analyzed the copy number alterations of tumor-related gene loci by array CGH, and their expressions in primary and transplanted AMLs.


METHODS
For the induction of AMLs, C3H/He Nrs mice were exposed to 3 Gy of x-rays or gamma-rays. The genomic alterations of 35 primary AMLs and 34 transplanted AMLs obtained from the recipient mice transplanted the primary AMLs were analyzed by array CGH. According to the genomic alterations and mutations of the 235th arginine of PU.1 allele, we classified the radiogenic AMLs into three types such as Chr2(del) PU.1(del/R235-) AML, Chr2(del) PU.1(del/R235+) AML and Chr2(intact) PU.1(R235+/R235+) AML, to compare the expression levels of 8 tumor-related genes quantitatively by real-time polymerase chain reaction and cell-surface antigen expression. Results. In addition to well-known loss of PU.1 with hemizygous deletion of chromosome 2, novel genomic alterations such as partial gain of chromosome 6 were recurrently detected in AMLs. In this study, we found similarity between cell-surface antigen expressions of bone marrows and those of spleens in AML mice and significantly higher expressions of c-myc and PU.1 expression, especially in the PU.1-deficient (Chr2(del) PU.1(del/R235-)) AML and Chr2(del) PU.1(del/R235+) compared to Chr2(intact) PU.1(R235+/R235+) AMLs.


CONCLUSIONS
The new finding on upregulation of c-myc and PU.1 in both and hemizygous PU.1-deficient AMLs and different genomic alterations detected by array CGH suggests that the molecular mechanism for development of radiation-induced AML should be different among three types of AML.
Hirouchi
Tokuhisa
T
Department of Radiobiology, Institute for Environmental Sciences, Hacchazawa, Takahoko, Rokkasho, Aomori, Japan. Hirouchi@ies.or.jp
Takabatake
Takashi
T
Yoshida
Kazuko
K
Nitta
Yumiko
Y
Nakamura
Masako
M
Tanaka
Satoshi
S
Ichinohe
Kazuaki
K
Oghiso
Yoichi
Y
Tanaka
Kimio
K
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000528:radiation effects*; D002869:Chromosome Aberrations / Q000528:radiation effects*; D033481:Chromosomes, Mammalian / Q000235:genetics*; D005720:Gamma Rays / Q000009:adverse effects*; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics / Q000528:radiation effects*; D016678:Genome / Q000528:radiation effects; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000528:radiation effects; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014965:X-Rays / Q000009:adverse effects*; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C489428:Myc protein, mouse