Abstract:
:LMO2 is a transcription regulator involved in human T-cell leukemia, including some occurring in X-SCID gene therapy trials, and in B-cell lymphomas and prostate cancer. LMO2 functions in transcription complexes via protein-protein interactions involving two LIM domains and causes a preleukemic T-cell development blockade followed by clonal tumors. Therefore, LMO2 is necessary but not sufficient for overt neoplasias, which must undergo additional mutations before frank malignancy. An open question is the importance of LMO2 in tumor development as opposed to sustaining cancer. We have addressed this using a peptide aptamer that binds to the second LIM domain of the LMO2 protein and disrupts its function. This specificity is mediated by a conserved Cys-Cys motif, which is similar to the zinc-binding LIM domains. The peptide inhibits Lmo2 function in a mouse T-cell tumor transplantation assay by preventing Lmo2-dependent T-cell neoplasia. Lmo2 is, therefore, required for sustained T-cell tumor growth, in addition to its preleukemic effect. Interference with LMO2 complexes is a strategy for controlling LMO2-mediated cancers, and the finger structure of LMO2 is an explicit focus for drug development.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Appert A,Nam CH,Lobato N,Priego E,Miguel RN,Blundell T,Drynan L,Sewell H,Tanaka T,Rabbitts Tdoi
10.1158/0008-5472.CAN-08-4774subject
Has Abstractpub_date
2009-06-01 00:00:00pages
4784-90issue
11eissn
0008-5472issn
1538-7445pii
69/11/4784journal_volume
69pub_type
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