Impairment of erythroid and megakaryocytic differentiation by a leukemia-associated and t(9;9)-derived fusion gene product, SET/TAF-Ibeta-CAN/Nup214.
SET-CAN associated with the t(9;9) in acute undifferentiated leukemia encodes almost the entire sequence of SET and the C-terminal two-third portion of CAN, including the FG repeat region. To clarify a role(s) of SET-CAN in leukemogenesis, we developed transgenic mice expressing SET-CAN under the control of the Gata1 gene hematopoietic regulatory domain that is active in distinct sets of hematopoietic cells. SET-CAN transgenic mice showed anemia, thrombocytopenia, and splenomegaly. A significant number of transgenic mice started dying after 6 months post-birth, being in good agreement with the fact that red blood cells and platelets decreased. We found that a significant number of c-kit+ myeloid cells appeared in peripheral blood in transgenic mice. Characterization of the bone marrow cells of transgenic mice indicated impairment in hematopoietic differentiation of erythroid, megakaryocytic, and B cell lineages by SET-CAN. Transgenic mice, in particular, exhibited a high population of the c-kit+Sca-1+Lin- fraction in bone marrow cells compared with that of the control littermates. Our results demonstrate that SET-CAN blocks the hematopoietic differentiation program--one of the characteristics of acute myeloid leukemia.
Saito
Shoko
S
Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Nouno
Kaoru
K
Shimizu
Ritsuko
R
Yamamoto
Masayuki
M
Nagata
Kyosuke
K
D000818:Animals; D002454:Cell Differentiation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D015672:Erythroid Precursor Cells / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology*; D056488:Histone Chaperones; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
D002868:Chromosomal Proteins, Non-Histone; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D028861:Nuclear Pore Complex Proteins; C490093:Nup214 protein, mouse; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C513473:SET protein, human; C481746:SET-CAN fusion protein, human; D014157:Transcription Factors