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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1350-1355
NEOPLASIA
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
Tomohito Yagi,
Shigeyoshi Hibi,
Mami Takanashi,
Gen Kano,
Yasuhiro Tabata,
Toshihiko Imamura,
Tohru Inaba,
Akira Morimoto,
Shinjiro Todo, and
Shinsaku Imashuku
From the Department of Pediatrics, Department of
Clinical Laboratory and Medicine, Kyoto Prefectural University of
Medicine, Kyoto, Japan; and Kyoto City Institute of Health and
Environmental Sciences, Kyoto, Japan.
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.
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