The TLX1 oncogene drives aneuploidy in T cell transformation.
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.
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
Kim
K
De Keersmaecker
Pedro J
PJ
Real
Giusy Della
GD
Gatta
Teresa
T
Palomero
Maria Luisa
ML
Sulis
Valeria
V
Tosello
Pieter
P
Van Vlierberghe
Kelly
K
Barnes
Mireia
M
Castillo
Xavier
X
Sole
Michael
M
Hadler
Jack
J
Lenz
Peter D
PD
Aplan
Michelle
M
Kelliher
Barbara L
BL
Kee
Pier Paolo
PP
Pandolfi
Dietmar
D
Kappes
Fotini
F
Gounari
Howard
H
Petrie
Joni
J
Van der Meulen
Frank
F
Speleman
Elisabeth
E
Paietta
Janis
J
Racevskis
Peter H
PH
Wiernik
Jacob M
JM
Rowe
Jean
J
Soulier
David
D
Avran
Hélène
H
Cavé
Nicole
N
Dastugue
Susana
S
Raimondi
Jules P P
JP
Meijerink
Carlos
C
Cordon-Cardo
Andrea
A
Califano
Adolfo A
AA
Ferrando
D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009929:Organ Size; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D032681:Spectral Karyotyping; D013601:T-Lymphocytes / Q000473:pathology*; D013950:Thymus Gland / Q000254:growth & development / Q000473:pathology; D014314:Trisomy / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
C479740:BCL11B protein, human; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C071250:TLX1 protein, human