Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

BACKGROUND: Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases. METHODS: The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output. RESULTS: In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea. CONCLUSIONS: PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.

Cord blood transplantation for adult mature lymphoid neoplasms in Europe and Japan.

ABSTRACT: To clarify the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n = 192; double CBT, n = 304; Japan: single CBT, n = 1150) in 2000-2017 were analyzed. Fewer patients with Hodgkin lymphoma (Europe vs Japan, 26% vs 5%), and older patients (≥50 years) (39% vs 59%) with a higher refined disease risk index (rDRI) (high-very high: 49% vs 14%) were included in the Japanese registry. High-very high rDRI was associated with inferior overall survival (OS) (vs low rDRI, Europe: hazard ratio [HR], 1.87; P = .001; Japan: HR, 2.34; P < .001) with higher progression/relapse risks. Total body irradiation (TBI)-containing conditioning contributed to superior OS both in Europe (vs TBI-reduced-intensity conditioning [RIC], non-TBI-RIC: HR, 1.93; P < .001; non-TBI-Myeloablative conditioning [MAC]: HR, 1.90; P = .003) and Japan (non-TBI-RIC: HR, 1.71; P < .001; non-TBI-MAC: HR 1.50, P = .007). The impact of HLA mismatches (≥2) on OS differed (Europe: HR, 1.52; P = .007; Japan: HR, 1.18; P = .107). CBT for lymphoid neoplasms, especially in those with high rDRI showed poor outcomes despite all the different characteristics in both registries. TBI should be considered in conditioning regimens to improve these outcomes. The different impacts of HLA mismatches call attention to the fundamental differences among these populations.

Scoring system for optimal cord blood unit selection for single cord blood transplantation.

BACKGROUND: We conducted a retrospective study to categorize the cord blood unit (CBU)s to identify the optimal units. METHODS: A total of 8503 adults (female, n = 3592; male, n = 4911) receiving their first single cord blood transplantation (CBT) in 2000-2019 were analyzed. Factors associated with CBUs affecting overall survival (OS) and neutrophil engraftment were selected to create ranked categorization for each outcome, followed by comparison with transplantation using HLA-matched bone marrow (BMT)/peripheral blood stem cell (PBSCT) from unrelated (n = 6052) and related donors (n = 4546). RESULTS: Sex-mismatch, CD34+ cell and CFU-GM counts were selected in the OS analysis. Considering the strong interaction between sex mismatch and CD34+ cell counts, we analyzed females and males separately. For females, female CBU with CD34+ cell counts {greater than or equal to} 0.5 × 10e5/kg and CFU-GM counts {greater than or equal to} 15 × 10e3/kg offered the best OS (Group I), followed by other groups with any (Groups II-IV) or all (Group V) of the risk factors. Group I consistently showed favorable OS (Group IV: HR1.22, P = 0.027; Group V: HR1.31, P = 0.047), comparable to those of rBMT/PBSCT (OS: HR1.02, P = 0.654) and uBM/PBSCT in patients with higher rDRI (HR1.07, P = 0.353). Male patients lacked significant factors affecting OS. Categorization for neutrophil engraftment consisting of CD34+ cell and CFU-GM counts, sex-mismatch, presence of donor-specific antibodies, and the number of HLA-mismatches was effective but not predicted OS. CONCLUSION: Our ranked categorizations sufficiently predicted female OS and engraftment. The best-ranked CBUs offered preferable outcomes comparable to conventional BM/PB donors in female but not in male patients.

Development of Conformationally Restricted Negamycin Derivatives for Potent Readthrough Activity.

(+)-Negamycin, which is a dipeptide-like antibiotic containing a hydrazide structure, exhibits readthrough activity, resulting in the restoration of dystrophin in the mdx mouse model of Duchenne muscular dystrophy (DMD). In our previous structure-activity relationship study of negamycin, we found that its natural analogue 3-epi-deoxynegamycin (TCP-107), without antimicrobial activity, showed a higher readthrough activity than negamycin. In this study, we designed and synthesized cyclopropane-based conformationally restricted derivatives of TCP-107 and evaluated their readthrough activity in the cell-based reporter assay against a TGA-type mutation derived from DMD. As a result, a down-cis isomer, TCP-304, showed significant readthrough activity among the four isomers. Moreover, TCP-306, a derivative acylated by l-α-aminoundecanoic acid, possessed approximately 3 times higher activity than TCP-304. These down-cis derivatives showed dose-dependent readthrough activity and were effective for not only TGA but also TAG mutations. These results suggest that the conformational restriction of negamycin derivatives by the introduction of the cyclopropane ring is effective for an exhibition of potent readthrough activity.

Impact of GVHD on lymphoma progression: Nationwide study from Japanese Society for Transplantation and Cellular Therapy.

The graft-versus-lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non-Hodgkin lymphomas (NHLs; indolent B-NHLs, n = 689; aggressive B-NHLs, n = 720; mature T/NK-NHLs, n = 795) receiving a first allo-HSCT in 2003-2017. Pre-transplant lymphoma control showed complete response (CR) in 759 and non-CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I-II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43-0.91), especially in mature T/NK-NHL (HR, 0.46; 95% CI, 0.26-0.83) and extensive cGVHD in patients with mature aggressive B-NHLs (HR, 0.55; 95% CI, 0.31-0.97). In total, limited cGVHD was associated with superior survivals (progression-free survival: HR, 0.71; 95% CI, 0.56-0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre-transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed.

Development of a Novel Indirect ELISA for the Serological Diagnosis of African Swine Fever Using p11.5 Protein as a Target Antigen.

African swine fever is a hemorrhagic viral disease with a mortality rate of nearly 100% in pigs. Hence, it is classified as a notifiable disease by the World Organization for Animal Health. Because no field-available vaccine exists, African swine fever virus (ASFV) control and eradication solely depend on good farm biosecurity management and rapid and accurate diagnosis. In this study, we developed a new indirect serological enzyme-linked immunosorbent assay (ELISA) using recombinant p11.5 protein from ASFV as a solid-phase target antigen. The cutoffs were determined by receiver operating curve analysis performed with serum samples obtained from naïve and infected pigs. Based on the results of a commercially available serological ELISA, the relative sensitivity and specificity of our assay were 93.4% and 94.4% (N = 166; area under the curve = 0.991; 95% confidence interval = 0.982-0.999), respectively. Furthermore, to compare the performance of the serological ELISAs, we conducted the assays on a panel of sera collected from pigs and boars experimentally infected with different ASFV isolates. The results indicated the greater sensitivity of the newly developed assay and its ability to detect anti-ASFV antibodies earlier after virus inoculation.

EDTA-induced pseudothrombocytopenia in hematopoietic stem cell donor.

We herein report a case of peripheral blood stem cell transplantation (PBSCT) involving a donor with EDTA-induced pseudothrombocytopenia (PTCP). The apheresis product was inspected for 24 h and there was no platelet clumping or thrombocytopenia. In the first 14 months after PBSCT, there has been no transfer of PTCP symptoms.

Postazacitidine clone size predicts long-term outcome of patients with myelodysplastic syndromes and related myeloid neoplasms.

Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n = 449) and posttreatment (n = 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P < .001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P = .009), and DDX41 mutation (HR, 0.33; 95% CI, 0.17-0.62; P < .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P < .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P < .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia.

Unrelated hematopoietic stem cell transplantation for familial platelet disorder/acute myeloid leukemia with germline RUNX1 mutations.

Germline mutations in RUNX1 result in rare autosomal-dominant familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). As genetic analysis is becoming increasingly prevalent, the diagnosis rate of FPD/AML is expected to increase. In this report, we present two pedigrees, one diagnosed molecularly and another highly suspected to be FPD/AML, whose members both received allogeneic hematopoietic stem cell transplantation (HSCT). Both pedigrees had a family history of thrombocytopenia, platelet dysfunction, and hematological malignancies. One family inherited a frameshift mutation (p.P240fs) of RUNX1, a known pathogenic variant. Another family inherited a point mutation (p.G168R) in the runt-homology domain, the clinical significance of which is uncertain at this point. As this mutation was completely absent from all population databases and had a relatively high REVEL score of 0.947, we thought that it would be dangerous to ignore its possible pathogenicity. Consequently, we avoided choosing HSCT donors from relatives of both families and performed HSCT from unrelated donors. In conclusion, our experience with two families of FPD/AML highlights the importance of searching for gene mutations associated with germline predisposition and indicates the necessity of developing a donor coordination system for FPD/AML patients, as well as a support system for families.

A Spontaneously Occurring African Swine Fever Virus with 11 Gene Deletions Partially Protects Pigs Challenged with the Parental Strain.

African swine fever (ASF) is an infectious Suidae disease caused by the ASF virus (ASFV). Adaptation to less susceptible, non-target host cells is one of the most common techniques used to attenuate virulent viruses. However, this may induce many mutations and large-scale rearrangements in the viral genome, resulting in immunostimulatory potential loss of the virus in vivo. This study continuously maintained the virulent ASFV strain, Armenia2007 (Arm07), to establish an attenuated ASFV strain with minimum genetic alteration in a susceptible host cell line, immortalized porcine kidney macrophage (IPKM). A mutant strain was successfully isolated via repeated plaque purification in combination with next-generation sequencing analysis. The isolated strain, Arm07ΔMGF, which was obtained from a viral fluid at a passage level of 20, lacked 11 genes in total in the MGF300 and MGF360 regions and showed marked reduction in virulence against pigs. Moreover, all the pigs survived the challenge with the parental strain when pigs were immunized twice with 105 TCID50 of Arm07ΔMGF, although viremia and fever were not completely prevented after the challenge infection. These findings suggest that this naturally attenuated, spontaneously occurring ASFV strain may provide a novel platform for ASF vaccine development.

Lenalidomide treatment for recurrent adult T-cell leukemia/lymphoma after allogeneic hematopoietic cell transplantation.

Patients with recurrent adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic cell transplantation (allo-HCT) have a dismal prognosis. We retrospectively evaluated the safety and efficacy of lenalidomide (LEN) in 11 consecutive patients with recurrent ATL after allo-HCT. The median time from allo-HCT to ATL recurrence was 111 days (range, 20-1476), and that from allo-HCT to the initiation of LEN was 162 days (range, 43-1560). The median initial daily dose of LEN was 10 mg (range, 5-25), and the median duration of LEN treatment was 37 days (range, 3-1078). Three patients (27%) achieved complete response and two (18%) achieved partial response (PR). The rates of complete or PR according to the involved site were 57% for skin and 50% for nodal or extranodal lesions. With a median follow-up of 1033 days (range, 601-1465) among survivors, the 1-year probability of overall survival (OS) after ATL recurrence was 55%. Grade ≥3 toxicities included cytopenia (n = 4), superficial vein thrombosis (n = 1), and deep vein thrombosis (n = 1). Graft-versus-host disease (GVHD) newly developed in five patients (45%) and worsened in four patients (36%). The median duration from the initiation of LEN to GVHD onset or worsening was 5 days (range, 1-9). GVHD was manageable in all patients. Seven patients received mogamulizumab (MOG) for recurrent ATL before LEN treatment. The overall response rates to LEN were 57% in patients who had previously received MOG and 25% in those who had not. The 1-year probabilities of OS after recurrent ATL were 71% in patients who had previously received MOG and 25% in those who had not. Although cytopenia and GVHD are common among patients with recurrent ATL after allo-HCT, LEN may improve survival. Administering MOG before LEN may augment treatment efficacy in the allo-HCT population.

Delivering mRNA to Secondary Lymphoid Tissues by Phosphatidylserine-Loaded Lipid Nanoparticles.

Lipid nanoparticles (LNPs) are one of the most successful technologies in messenger RNA (mRNA) delivery. While the liver is the most frequent target for LNP delivery of mRNA, technologies for delivering mRNA molecules to extrahepatic tissues are also important. Herein, it is reported on the development of an LNP that targets secondary lymphoid tissues. New types of alcohol-soluble phosphatidylserine (PS) derivatives are designed as materials that target immune cells and then incorporated into LNPs using a microfluidic technique with a high degree of scalability and reproducibility. The resulting LNP that contained the synthesized PS delivered mRNA to the spleen much more efficiently compared to a control LNP. A sub-organ analysis revealed that the PS-loaded LNP is extensively taken up by tissue-resident macrophages in the red pulp and the marginal zone of the spleen. Thus, the PS-loaded LNP reported in this study will be a promising strategy for clinical applications that involve delivering mRNA to the spleen.

Helix-forming aliphatic homo-δ-peptide foldamers based on the conformational restriction effects of cyclopropane.

Considerable effort has been directed toward developing artificial peptide-based foldamers. However, detailed structural analysis of δ-peptide foldamers consisting of only aliphatic δ-amino acids has not been reported. Herein, we rationally designed and stereoselectively synthesized aliphatic homo-δ-peptides forming a stable helical structure by using a chiral cyclopropane δ-amino acid as a monomer unit. Structural analysis of the homo-δ-peptides using circular dichroism, infrared, and NMR spectroscopy indicated that they form a stable 14-helical structure in solution. Furthermore, we successfully conducted X-ray crystallographic analysis of the homo-δ-peptides, demonstrating a right-handed 14-helical structure. This helical structure of the crystal was consistent with those predicted by theoretical calculations and those obtained based on NMR spectroscopy in solution. This stable helical structure is due to the effective restriction of the backbone conformation by the structural characteristics of cyclopropane. This work reports the first example of aliphatic homo-δ-peptide foldamers having a stable helical structure both in the solution and crystal states.

Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside.

Investigating the neurocircuit and synaptic sites of action of oxytocin (OT) in the brain is critical to the role of OT in social memory and behavior. To the same degree, it is important to understand how OT is transported to the brain from the peripheral circulation. To date, of these, many studies provide evidence that CD38, CD157, and receptor for advanced glycation end-products (RAGE) act as regulators of OT concentrations in the brain and blood. It has been shown that RAGE facilitates the uptake of OT in mother's milk from the digestive tract to the cell surface of intestinal epithelial cells to the body fluid and subsequently into circulation in male mice. RAGE has been shown to recruit circulatory OT into the brain from blood at the endothelial cell surface of neurovascular units. Therefore, it can be said that extracellular OT concentrations in the brain (hypothalamus) could be determined by the transport of OT by RAGE from the circulation and release of OT from oxytocinergic neurons by CD38 and CD157 in mice. In addition, it has recently been found that gavage application of a precursor of nicotinamide adenine dinucleotide, nicotinamide riboside, for 12 days can increase brain OT in mice. Here, we review the evaluation of the new concept that RAGE is involved in the regulation of OT dynamics at the interface between the brain, blood, and intestine in the living body, mainly by summarizing our recent results due to the limited number of publications on related topics. And we also review other possible routes of OT recruitment to the brain.

Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents.

Resolvins are pro-resolving lipid mediators with highly potent anti-inflammatory effects. Because of their polyunsaturated structures, however, they are unstable to oxygen as a drug prototype. To address this issue, we designed and synthesized CP-RvE3 as oxidatively stable congeners of RvE3 by replacing the cis-olefin with a cis-cyclopropane to avoid the unstable bisallylic structure. Although the oxidative stabilities of CP-RvE3 were not improved, ß-CP-RvE3 was 3.7 times more metabolically stable than RvE3. Thus, we identified ß-CP-RvE3 as a metabolically stable equivalent.

Synthesis of γ-Aminobutyric Acid (GABA) Analogues Conformationally Restricted by Bicyclo[3.1.0]hexane/hexene or [4.1.0]Heptane/heptene Backbones as Potent Betaine/GABA Transporter Inhibitors.

Novel γ-aminobutyric acid (GABA) analogues 3-5, having a bicyclo[3.1.0]hexene, [4.1.0]heptane, or [4.1.0]heptene backbone, respectively, were designed from the bioactive form analysis of the previous inhibitor 2 with a bicyclo[3.1.0]hexane backbone. Compounds 3-5 and 2 were synthesized from a common 1,7-diene intermediate 6 using ring-closing metathesis (RCM) to construct the key bicyclo backbones. Compounds 3-5 strongly inhibit betaine/GABA transporter 1 (BGT1) uptake, but compound 4 stands out with its selective low micromolar potency.

Development of enzyme/titanate nanosheet complex coated with molecularly imprinted polydopamine for colorimetric quercetin assay.

A novel hybrid material, which is an enzyme/inorganic nanosheet complex coated by molecularly imprinted polymer (MIP), was developed, and applied to colorimetric quercetin assay. First, an enzyme/inorganic nanosheet complex was prepared from horseradish peroxidase (HRP) enzyme and titanate nanosheet (TiOx), using electrostatic interactions between them in acetate buffer. In the next place, dopamine self-polymerization was performed in the presence of HRP/TiOx complex with quercetin as a template, to prepare MIP membrane onto the HRP/TiOx complex. After washing process, a new hybrid material, MIP-coated HRP/TiOx complex (MIP-HT) was obtained. MIP-HT adsorbed quercetin efficiently, compared with NIP-HT that is an HRP/TiOx complex coated with non-imprinted polydopamine. MIP-HT showed enzymatic activity for an oxidation reaction of guaiacol, which is a chromogenic substrate of HRP, whereas the enzymatic activity of NIP-HT was significantly suppressed. The amount of brown product, formed by the color reaction, reduced owing to the presence of quercetin in sample solution, and a good liner relationship was observed between the concentration of quercetin and the increment of absorbance at 470 nm. The investigation using several biomolecules indicates that MIP-HT has the ability to detect quercetin and its analogues with selectivity. Therefore, MIP-HT shows great promise as a new and attractive material for use in colorimetric assay of quercetin or quercetin analogues.

HLA 1-3 antigen-mismatched related peripheral blood stem cells transplantation using low-dose antithymocyte globulin versus unrelated cord blood transplantation.

Little information is available regarding whether unrelated cord blood transplantation (CBT) or an HLA 1-3 antigen-mismatched related donor peripheral blood stem-cell transplantation (PBSCT) using low-dose anti-thymocyte globulin (ATG) is superior as an alternative transplantation for patients who lack an HLA-matched sibling or unrelated donor. Therefore, we evaluated 7861 patients with hematologic malignancies (aged 0 to 70 years) who received either a CBT without ATG (CBT-no ATG, n = 7034) or an HLA 1-3 antigen-mismatched related donor PBSCT using low-dose ATG (PBSCT-ATG, n = 827). CBT-no ATG was associated with significantly better overall survival (OS) than the use of a PBSCT-ATG (hazard ratio [HR], 0.77; p < .001), although PBSCT-ATG patients with an HLA 1 antigen-mismatch showed OS comparable to that in the CBT-no ATG group. Neutrophil and platelet engraftment was significantly delayed, whereas the incidences of nonrelapse mortality, and severe graft-versus-host disease (GVHD) were significantly lower in the CBT-no ATG group. The incidences of relapse and chronic GVHD were comparable between these donors. In conclusion, CBT-no ATG may be a better alternative than HLA-mismatched related donor PBSCT using low-dose ATG. Notably, HLA 2-3 antigen mismatch-related transplantation with low-dose ATG had significant adverse effects on transplantation outcomes.

Improvement in the Physical Function and Quality of Life through Exercise and Physical Activity Intervention Using a Smartphone after Allogeneic Hematopoietic Cell Transplantation: A Case Report.

PURPOSE: Physical activity (PA) interventions positively affect the physical function (PF) in patients with advanced cancer. However, patients must remain motivated during the intervention. We report a case wherein a smartphone application for PA intervention was useful in motivating the patient to improve adherence. METHODS: A 40-year-old woman underwent an allogeneic hematopoietic cell transplantation (allo-HCT) for an advanced extranodal natural killer/T-cell lymphoma. On day 6, she developed the posterior reversible encephalopathy syndrome. She was managed in the intensive care unit for 3 days, and her PF declined markedly. We initiated a smartphone-based PA intervention from day 35. She was instructed to maintain a PA diary for self-monitoring of the daily steps and to set a new step-count goal every week. RESULTS: The PA and PF improved within a short period thereafter. However, she developed severe acute graft-versus-host disease and was administered with high-dose systemic corticosteroids from day 49. The PA, PF, and quality of life (QOL) decreased again. The intervention was continued for 5 months with a high adherence. The PA, PF, and QOL improved gradually. She resumed independent activities of daily living and was discharged on day 202. CONCLUSION: Smartphone-based PA intervention may be effective against post-allo-HCT physical dysfunction.

Whole-genome landscape of adult T-cell leukemia/lymphoma.

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.