Cobb angle outcomes in adolescent idiopathic scoliosis curves above the seventh/eighth thoracic vertebrae: A comparison of Milwaukee and Chêneau bracing techniques.

Overall survival for children diagnosed with acute lymphoblastic leukemia (ALL) is now above 90%. However, this statistic can be misleading because not all genetic subtypes of ALL patients share in this success. Amongst the worst are children diagnosed with TCF3::HLF‐positive B‐cell ALL (B‐ALL), arising from the translocation t(17;19)(q22;p13). Although rare at less than 1% of cases, these patients have a 5‐year event‐free survival of approximately 25%, respond poorly to induction chemotherapy and essentially fatal at relapse., , This TCF3::HLF fusion has been shown to rewire the transcriptional program in committed lymphoid progenitors towards a stem‐like, myeloid‐biased state, overwhelmingly by binding to enhancer elements in intronic and intergenic regions rather than at promoters., However, direct links between TCF3::HLF‐bound enhancers and target genes have remained unclear. Furthermore, progress on understanding the early steps of TCF3::HLF‐driven leukemogenesis has in part been due to the inability to generate a genetically engineered mouse model. Now two new studies, provide new mechanistic insight on how the TCF3::HLF fusion drives leukemogenesis and supports cell proliferation. In the first study by Priebe et al., the authors provide a comprehensive three‐dimensional map of the TCF3::HLF regulome. Using TCF3::HLF‐HiChIP in HAL‐01 cells, they demonstrate that 94% of bound sites were within intronic or intergenic regions enriched at chromatin with H3K27ac and H3K4me1 that demarcate enhancers. The authors then ranked the interactions by cumulative contact frequency and found (myocyte enhancer factor 2C) at the very top of this list. The functional importance of this interaction and was validated using CRISPR‐mediated disruption of the HLF binding motif within the intragenic enhancer. This selectively decreased the proliferation of HAL‐01 cells but not in 697 cells harboring the related TCF3::PBX1 fusion. Direct knockout reproduced the same block in HAL‐01 and a second TCF3::HLF‐positive cell line YCUB‐2 and was equivalent to loss of TCF3::HLF itself. This new data suggests that a single enhancer–promoter interaction in the MEF2C locus sits at the apex of the TCF3::HLF oncogenic hierarchy, sustaining a self‐renewal program as essential to leukemia maintenance as the fusion protein itself (Figure ). Aberrant activation of is additionally associated with bone destruction. Nascent transcription profiling approaches, such as PRO‐seq, could be used to identify enhancer RNAs (eRNAs) arising from these fusion‐bound regulatory elements. These eRNAs (if present) may represent selective therapeutic targets, where antisense oligonucleotides (ASOs) could be leveraged to suppress and expression indirectly, thereby mitigating any on target, off tumor toxicity associated with direct inhibition of either MEF2C or IL‐1β.