Shinya Endo

Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is the only curative approach for adult T‐cell leukemia‐lymphoma (ATL). However, preventing post‐transplant relapse remains challenging. While pre‐transplant disease status is known to be associated with post‐transplant outcomes, the impact of residual disease (RD) localization at the time of allo‐HCT has not been well described. In this retrospective study of 33 patients with aggressive ATL who underwent allo‐HCT, patients were classified into two risk groups based on RD sites: a low‐risk group (no lymph node [LN] or extranodal [EN] disease, regardless of the presence of peripheral blood disease) and a high‐risk group (presence of LN and/or EN disease). The low‐risk group had significantly superior overall survival (OS) and progression‐free survival (PFS) compared to the high‐risk group, with longer median survival times (OS: 1953 vs. 245 days; PFS: 1177.5 vs. 72 days) and higher 2‐year survival rates (OS: 65.0% vs. 11.3%; PFS: 50.0% vs. 8.3%) ( p = 0.012 and p = 0.013, respectively). Furthermore, even among patients who had not achieved complete response, RD localization stratified the survival outcomes: the 2‐year OS and PFS were 75.0% and 75.0% in the low‐risk group, compared with 11.3% and 8.3% in the high‐risk group, respectively. In conclusion, RD localization at the time of allo‐HCT is a novel prognostic factor, highlighting the need for tailored pre‐transplant management for ATL.

Objectives: CCAAT/enhancer‐binding protein α (CEBPA) is an essential transcription factor for myeloid differentiation. Not only mutation of the CEBPA gene, but also promoter methylation, which results in silencing of CEBPA, contributes to the pathogenesis of acute myeloid leukemia (AML). We sought for another differentially methylated region (DMR) that associates with the CEBPA silencing and disease phenotype.Methods: Using databases, we identified a conserved DMR in the CEBPA 3′‐untranslated region (UTR).Results: Methylation‐specific PCR analysis of 231 AML cases showed that hypermethylation of the 3′‐UTR was associated with AML that had a myeloid/NK/T‐cell phenotype and downregulated CEBPA. Most of these cases were of an immature phenotype with CD7/CD56 positivity. These cases were significantly associated with lower hemoglobin levels than the others. Furthermore, we discovered that the CEBPA 3′‐UTR DMR can enhance transcription from the CEBPA native promoter. In vitro experiments identified IKZF1‐binding sites in the 3′‐UTR that are responsible for this increased transcription of CEBPA.Conclusions: These results indicate that the CEBPA 3′‐UTR DMR is a novel regulatory element of CEBPA related to myeloid/NK/T‐cell lineage leukemogenesis. Transcriptional regulation of CEBPA by IKZF1 may provide a clue for understanding the fate determination of myeloid vs. NK/T‐lymphoid progenitors.