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Next Article 
Transcription factors, translocations, and leukemia
J Nichols and SD Nimer
Department of Medicine, UCLA School of Medicine 90024-1678.
The frequent occurrence of TF gene involvement in translocations associated
with leukemia is remarkable, although not yet explained. The wide variety
of TFs involved in these translocations and the different stages of
cellular maturation argue against a unifying mechanism. Recombinases,
active during B-cell and T-cell development, have been implicated in gene
arrangements involving TCR genes and in the SIL/SCL rearrangement, which
involves two genes not normally rearranged. However, other mechanisms must
clearly be active in generating these molecular abnormalities and perhaps
they relate to the multistep maturation and differentiation processes and
continuous cell turnover seen in hematopoietic cells. The difficulties in
obtaining human solid tumor samples may make it more difficult to identify
translocations involving TF genes in solid tumors. Recently, the
cytogenetic analysis of solid tumors has improved and specific cytogenetic
abnormalities have been associated with specific types of tumors. With
advanced techniques, such as fluorescent in situ hybridization (a technique
that does not depend on cell growth) and PCR, abnormalities involving TF
genes will be discovered. Abnormalities of TF genes, other than
translocations, have been seen in a broad variety of nonhematopoietic
malignancies. The p53 protein has been shown to bind DNA in a sequence-
specific fashion and interact with a variety of DNA tumor virus
oncoproteins. The broad range of cell types that harbor p53 abnormalities
suggests that TF abnormalities will likely be implicated in many solid
tumors. We have detailed several examples of how gene rearrangements that
accompany chromosomal translocations in acute leukemia can alter the
expression or activity of cellular TFs. Several translocations generate
fusion RNA transcripts and fusion TF proteins with altered functional
characteristics. Other translocations result in the expression of a gene
not normally detectable in hematopoietic cells or alter the level of its
expression, or affect the promoter usage or exon structure of the gene
(Table 2). Studies are underway in many laboratories to characterize the
biologic activity of these abnormal TFs and it remains to be proven that
these molecular abnormalities are directly linked with leukemogenesis. The
identification of abnormal fusion transcripts and proteins may allow
specific therapies to be directed against "tumor-specific" DNA, mRNA, or
protein targets. Therapeutic strategies based on antisense or ribozyme
technology may be used to turn off expression of these genes and inhibit
leukemia cell growth. Immunologic methods can also be used to direct
therapy against the malignant cells.
Volume 80,
Issue 12,
pp. 2953-2963,
12/15/1992
Copyright © 1992 by The American Society of Hematology
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