Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform–specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3′-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell–like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

At onset, myelodysplastic syndrome (MDS) may be complicated by coagulation and fibrinolytic abnormalities, such as disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), infection, thromboembolism, hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (HPS/HLH), hemorrhage, and hematoma formation. In these cases, the cause may be secondary. On the other hand, it is known that platelet clotting dysfunction and fibrinolysis abnormalities are seen in the background of MDS, and primary fibrinolysis abnormalities may be complicated by adverse events associated with paraneoplastic syndrome (PNS). Coagulation fibrinolysis, as a PNS associated with MDS, is known to take the pattern of either consumptive coagulation abnormality or fibrinolytic coagulation abnormality. One mechanism of coagulation and fibrinolytic abnormalities has been shown to be the immunophenotypical pathway, and aberrant cytokine production is also associated with coagulopathy in MDS. We focused on how to differentiate an MDS-associated bleeding tendency resulting from either secondary or primary causes. In order to make this differentiation, we proposed a useful flowchart for the differentiation of solidified fibrinolysis seen at the initial MDS diagnosis. Additionally, we compared and summarized the molecular pathways of the secondary and primary causes of coagulopathy. Addressing coagulation and fibrinolytic abnormalities in MDS is required to differentiate the complexity and heterogeneity of bleeding and coagulation abnormalities. This review highlights the need to distinguish between the primary (disease-intrinsic) and secondary (reactive or complication-related) causes of coagulopathy. By proposing a diagnostic flowchart tailored to evaluate these causes at initial diagnosis, this study supports individualized risk stratification and management strategies. By comparing the molecular pathways of the two causes of coagulopathy, we provide a clinical discussion of the underlying pathologies. This aligns with the principles of personalized medicine by ensuring that treatment decisions (e.g., supportive care, anticoagulation, and antifibrinolytics) are based on the patient’s specific pathophysiological profile, rather than a one-size-fits-all approach.

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.