Lauwereins Lukas, Van Thillo Quentin, Demeyer Sofie, Mentens Nicole, Provost Sarah, Jacobs Kris, Gielen Olga, Boogaerts Lien, de Bock Charles E, Andrieu Guillaume, Asnafi Vahid, Cools Jan, Veloso Alexandra
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Center for Cancer Biology, VIB, Leuven, Belgium.
Leukemia. 2025 Mar;39(3):568-576. doi: 10.1038/s41375-025-02513-w. Epub 2025 Jan 21.
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.
T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液疾病，起源于T细胞祖细胞的恶性转化，由基因畸变的积累所致。五分之一的T-ALL患者具有同源框转录因子TLX3的异位表达特征。然而，TLX3在T-ALL中的作用仍不清楚，部分原因是缺乏合适的研究模型。引人注目的是，在儿科病例中，这个TLX3阳性亚组FLT3突变频率很高，主要是FLT3-ITD。为了对此进行研究，我们通过共表达TLX3和FLT3-ITD生成了体外培养的前T细胞，这赋予了细胞IL7非依赖性生长能力。这个模型使我们能够证实TLX3表达和FLT3信号传导协同作用转化T细胞并诱导致癌环境。来自这个细胞模型的数据，结合TLX3阳性T-ALL病例的基因表达数据，揭示了转录抑制因子TLE4的强烈下调。此外，TLE4对体外TLX3 T-ALL细胞生长具有抑制作用，这可能是由TLX3转录谱的部分逆转引起的。总之，我们开发了一个TLX3+FLT3-ITD前T细胞模型，并利用它来说明TLX3直接抑制TLE4表达，这对TLX3的致癌功能有益。
