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.
De Keersmaecker
Kim
K
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
Real
Pedro J
PJ
Gatta
Giusy Della
GD
Palomero
Teresa
T
Sulis
Maria Luisa
ML
Tosello
Valeria
V
Van Vlierberghe
Pieter
P
Barnes
Kelly
K
Castillo
Mireia
M
Sole
Xavier
X
Hadler
Michael
M
Lenz
Jack
J
Aplan
Peter D
PD
Kelliher
Michelle
M
Kee
Barbara L
BL
Pandolfi
Pier Paolo
PP
Kappes
Dietmar
D
Gounari
Fotini
F
Petrie
Howard
H
Van der Meulen
Joni
J
Speleman
Frank
F
Paietta
Elisabeth
E
Racevskis
Janis
J
Wiernik
Peter H
PH
Rowe
Jacob M
JM
Soulier
Jean
J
Avran
David
D
Cavé
Hélène
H
Dastugue
Nicole
N
Raimondi
Susana
S
Meijerink
Jules P P
JP
Cordon-Cardo
Carlos
C
Califano
Andrea
A
Ferrando
Adolfo A
AA
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