[en] T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease originating from the malignant transformation of T-cell progenitors, caused by the accumulation of genetic aberrations. One-fifth of T-ALL patients are characterized by ectopic expression of the homeobox transcription factor TLX3. However, the role of TLX3 in T-ALL remains elusive, partly due to the lack of suitable study models. Strikingly, this TLX3-positive subgroup has a high frequency of FLT3 mutations, predominantly FLT3-ITD, in pediatric cases. To investigate this, we generated ex vivo cultured pro-T cells driven by the co-expression of TLX3 and FLT3-ITD, which conferred IL7 independent growth. This model allowed us to confirm that TLX3 expression and FLT3 signaling cooperate to transform T-cells and induce an oncogenic context. Data from this cell model, combined with gene expression data from TLX3 positive T-ALL cases, revealed a strong downregulation of the transcriptional repressor TLE4. Furthermore, TLE4 showed to have a repressive effect on ex vivo TLX3 T-ALL cell growth, likely caused by a partial reversal of the TLX3 transcriptional profile. In conclusion, we developed a TLX3+FLT3-ITD pro-T cell model and used it to illustrate that TLX3 directly represses TLE4 expression, which is beneficial for the oncogenic function of TLX3.
Disciplines :
Genetics & genetic processes
Author, co-author :
Lauwereins, Lukas ; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Van Thillo, Quentin ; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Demeyer, Sofie; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Mentens, Nicole ; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Provost, Sarah; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Jacobs, Kris ; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Gielen, Olga ; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
Boogaerts, Lien; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium
de Bock, Charles E ; Department of Human Genetics, KU Leuven, Leuven, Belgium ; Center for Cancer Biology, VIB, Leuven, Belgium ; Children's Cancer Institute, UNSW Sydney, Sydney, NSW, Australia
Andrieu, Guillaume; Institute Necker Enfants-Malades, INSERM U1151, Paris, France
Asnafi, Vahid; Institute Necker Enfants-Malades, INSERM U1151, Paris, France ; Laboratoire d'Onco-Hématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
Cools, Jan ; Department of Human Genetics, KU Leuven, Leuven, Belgium. jan.cools@kuleuven.be ; Center for Cancer Biology, VIB, Leuven, Belgium. jan.cools@kuleuven.be
Bacquelaine Veloso, Alexandra ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie ; Department of Human Genetics, KU Leuven, Leuven, Belgium. alexandra.bacquelaineveloso@kuleuven.be ; Center for Cancer Biology, VIB, Leuven, Belgium. alexandra.bacquelaineveloso@kuleuven.be
FWO - Fonds Wetenschappelijk Onderzoek Vlaanderen Stichting Tegen Kanker
Funding text :
We thank Dr Thomas M\u00FCller from the Max-Delbr\u00FCck-Centrum of Molecular Medicine (MDC) in Berlin for kindly providing us with the custom made TLX3 antibody. We thank the VIB flow cytometry core and KU Leuven genomics core for the support in processing the data obtained during this study. The graphical abstract was created using BioRender.com. This work was supported by a FWO fellowship to QVT, a postdoctoral fellowship to SD by the Foundation against Cancer, a postdoctoral FWO fellowship to AV, and a research grant by FWO to JC.
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