High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis.
While studying Ikaros proteins in childhood acute myeloid leukemia (AML), Ikaros isoform 6 (Ik6) expression was detected in 7 of 10 cases of M4 and M5 leukemia, but in none of the remaining French-American-British subtypes (M2, 8 cases; M7, 6 cases). The spliced Ikaros isoforms 4 to 8 (Ik4-8) suppress the function of full-length Ik1 or Ik2 in a dominant-negative manner, owing to their reduced numbers of DNA binding sites. Thus, dominant-negative Ikaros isoforms may inhibit the normal transcriptional regulation of hematopoietic cell development. To clarify the function of Ik6 in developing blood cells, this isoform was transiently transfected into an Ik2(+), interleukin-3 (IL-3)-dependent 32D murine myeloid precursor cell line and studied the expression of Bcl-2 family proteins in relation to in vitro cell growth, using a tetracycline-inducible TREx system. The possibility of aberrant cell regulation due to Ikaros functional changes was examined by cotransfecting both Ik2 and Ik6 into Ikaros/Aiolos/Helios triple-negative Cos-7 cells. The results demonstrated IL-3-independent growth by Ik6-transfected 32D clones coincident with up-regulation of the antiapoptotic protein Bcl-XL. Up-regulation of Bcl-XL, but not of other Bcl-2 family proteins, was associated with the suppression of functional Ik2 by Ik6 in a dominant-negative fashion. Thus, the pathogenesis of myelomonocytic/monocytic AML may involve aberrant regulation of apoptosis due to unscheduled expression of the Ik6 isoform.
Yagi
Tomohito
T
Department of Pediatrics, Department of Clinical Laboratory and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. tyagi@gan2.res.ncc.go.jp
Hibi
Shigeyoshi
S
Takanashi
Mami
M
Kano
Gen
G
Tabata
Yasuhiro
Y
Imamura
Toshihiko
T
Inaba
Tohru
T
Morimoto
Akira
A
Todo
Shinjiro
S
Imashuku
Shinsaku
S
D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001773:Blood Cells / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D051740:Ikaros Transcription Factor; D007223:Infant; D007948:Leukemia, Monocytic, Acute / Q000209:etiology / Q000235:genetics*; D015479:Leukemia, Myelomonocytic, Acute / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051020:bcl-X Protein; D051740:Ikaros Transcription Factor