{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTLX1 (also known as HOX11) is a homeodomain transcription factor that plays a central oncogenic role in T‐cell acute lymphoblastic leukemia (T‐ALL). In leukemic cells, its aberrant expression contributes to transformation by several mechanisms. For example, TLX1 directly downregulates critical genes governing the mitotic checkpoint—such as CHEK1—thereby promoting chromosomal missegregation and aneuploidy early in tumor development. In parallel, TLX1 helps to establish a master oncogenic transcriptional network by collaborating with other factors (including its paralog TLX3), mediating a block in T‐cell receptor (TCR) rearrangement through interaction with ETS1, and cooperating with activated signaling pathways (such as those driven by NOTCH1 and NUP214-ABL1/STAT5) to activate proto‐oncogenes like MYC and BCL2. These findings, as demonstrated in diverse transgenic and primary human T‐ALL models, highlight TLX1’s dual role in both the initiation and partial maintenance of the leukemic phenotype."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its impact on cell cycle and differentiation arrest, TLX1’s oncogenic function is further mediated by its interactions with a variety of transcriptional cofactors. Its activity may vary in a concentration‐ and context‐dependent manner—for instance, differential regulation of target genes such as FHL1 and NR4A3 has been linked to the level of TLX1 expression. TLX1 can physically interact with Gro/TLE family proteins through an Eh1‐like motif to counteract repressor complexes (for example those formed by HES1), and it also engages with MEIS proteins that are co‐expressed in T‐ALL. Upstream regulatory elements involving PBX2 and PREP1 have been implicated in controlling TLX1 transcription, underscoring the complexity of its regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn broader biological contexts, TLX1 not only drives T‐lineage leukemogenesis but is also implicated in developmental and genomic regulatory mechanisms. In certain T-ALL subsets, variations in TLX1 (or the closely related HOX11L2) expression delineate distinct oncogenic groups with prognostic significance. Genomic studies have revealed that DNA secondary structures (such as G-quadruplex motifs) at the HOX11/ TLX1 breakpoint may underlie its susceptibility to chromosomal rearrangements. In nonleukemic settings, TLX1 expression is detected in adult splenic stem cells and in erythroid progenitors, where it modulates differentiation via interactions with cofactors like CBP—and its expression is subject to dynamic epigenetic regulation (for instance, increased promoter methylation in the placenta correlates with decreasing mRNA levels). Moreover, TLX1 overexpression can cooperate with defects in spindle checkpoint components (including through interactions with genes such as Ubr1) to exacerbate chromosomal instability, while gene expression profiling has defined a TLX1-driven proliferative signature. Although TLX1’s principal pathological role is in T‐ALL and T‐lymphoblastic lymphoma, related TLX family members have also been implicated in other malignancies (for example, androgen insensitivity in castration‐resistant prostate cancer), and genetic polymorphisms in TLX1 may contribute to leukemia risk in pediatric patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kim De Keersmaecker, Pedro J Real, Giusy Della Gatta, et al. 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