Targeting LMO2 with a peptide aptamer establishes a necessary function in overt T-cell neoplasia.
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.
Appert
Alex
A
Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Nam
Chang-Hoon
CH
Lobato
Natividad
N
Priego
Eva
E
Miguel
Ricardo Nunez
RN
Blundell
Tom
T
Drynan
Lesley
L
Sewell
Helen
H
Tanaka
Tomoyuki
T
Rabbitts
Terence
T
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D052158:Aptamers, Peptide / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D052158:Aptamers, Peptide; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C513188:Lmo2 protein, mouse; D008667:Metalloproteins