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Secondary Mutation Maintains the Transformed State in BaF3 Cells
With Inducible BCR/ABL Expression
Kevin M. Klucher,
David V. Lopez, and
George Q. Daley
From the Whitehead Institute for Biomedical Research, Cambridge,
MA.
The BCR/ABL gene product of the Philadelphia (Ph) chromosome induces
chronic myelogenous leukemia (CML). We generated a hematopoietic cell
line, TonB210.1, with tetracycline-dependent BCR/ABL expression to
investigate the pathways by which BCR/ABL transforms cells. TonB210.1
demonstrates conditional growth factor independence in tissue culture
and rapidly forms tumors in mice fed the tetracycline analog
doxycycline. The tumors regress completely upon doxycycline withdrawal,
but ultimately reform in all animals. After a long latency, tumors also
develop in animals never exposed to doxycycline. Subclones of TonB210.1
established from doxycycline-independent tumors demonstrate distinct
mechanisms of transformation. Most subclones manifest increased basal
levels of BCR/ABL expression; some have lost the capacity to augment
expression upon induction, whereas others remain inducible. More
interestingly, some subclones maintain tight conditional expression of
BCR/ABL and are therefore transformed by secondary mechanisms that no
longer require BCR/ABL expression. These subclones show constitutive
phosphorylation of the STAT5 protein, suggesting that activating
mutations have occurred upstream in the signaling pathway to STAT5. The
tight conditional expression of BCR/ABL in the TonB210.1 cell line
affords the opportunity to study several interesting aspects of the
biology of BCR/ABL, including activation of critical signaling pathways and transcriptional programs, and its potential role in genomic instability.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3927-3934
© 1998 by The American Society of Hematology.
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