TY - JOUR
T1 - The TLX1 oncogene drives aneuploidy in T cell transformation
AU - De Keersmaecker, Kim
AU - Real, Pedro J.
AU - Gatta, Giusy Della
AU - Palomero, Teresa
AU - Sulis, Maria Luisa
AU - Tosello, Valeria
AU - Van Vlierberghe, Pieter
AU - Barnes, Kelly
AU - Castillo, Mireia
AU - Sole, Xavier
AU - Hadler, Michael
AU - Lenz, Jack
AU - Aplan, Peter D.
AU - Kelliher, Michelle
AU - Kee, Barbara L.
AU - Pandolfi, Pier Paolo
AU - Kappes, Dietmar
AU - Gounari, Fotini
AU - Petrie, Howard
AU - Van Der Meulen, Joni
AU - Speleman, Frank
AU - Paietta, Elisabeth
AU - Racevskis, Janis
AU - Wiernik, Peter H.
AU - Rowe, Jacob M.
AU - Soulier, Jean
AU - Avran, David
AU - Cavé, Hélène
AU - Dastugue, Nicole
AU - Raimondi, Susana
AU - Meijerink, Jules P.P.
AU - Cordon-Cardo, Carlos
AU - Califano, Andrea
AU - Ferrando, Adolfo A.
PY - 2010/10
Y1 - 2010/10
N2 - The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
AB - The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
KW - Aneuploidy
KW - Animals
KW - Base Sequence
KW - Cell Transformation, Neoplastic/genetics
KW - Chromosome Aberrations
KW - Comparative Genomic Hybridization
KW - DNA Mutational Analysis
KW - Gene Deletion
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Leukemic
KW - Homeodomain Proteins/genetics
KW - Mice
KW - Mice, Transgenic
KW - Molecular Sequence Data
KW - Organ Size
KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
KW - Proto-Oncogene Proteins/genetics
KW - Repressor Proteins/genetics
KW - Spectral Karyotyping
KW - T-Lymphocytes/pathology
KW - Thymus Gland/growth & development
KW - Trisomy/genetics
KW - Tumor Suppressor Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=78149348102&partnerID=8YFLogxK
U2 - 10.1038/nm.2246
DO - 10.1038/nm.2246
M3 - Article
C2 - 20972433
AN - SCOPUS:78149348102
SN - 1078-8956
VL - 16
SP - 1321
EP - 1327
JO - Nature Medicine
JF - Nature Medicine
IS - 11
ER -