Ludovic LHERMITTE

Neopterin levels and kynurenine/tryptophan ratios (KTRs) increase with IFN-γ stimulation, indicating TH1 immunity, and thus might be inversely associated with asthma. We sought to examine the association of maternal neopterin levels and KTRs during pregnancy with asthma in the offspring. We analyzed the associations of maternal plasma total neopterin levels and KTRs in midpregnancy with asthma at age 7 years among 2883 children in the Norwegian Mother and Child Cohort Study. Asthma was classified either based on registered dispensed asthma medications in the Norwegian Prescription Database or maternal report. We calculated adjusted relative risks using log-binomial regression. The median gestational week of blood sampling was 18 weeks (interquartile range, 17-19 weeks). The risk of dispensed asthma medications at age 7 years was highest among children of mothers in the highest quartile of neopterin levels, whereas the risk was similar in the 3 lowest quartiles. The adjusted relative...

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

Lack of progress in curing AML is likely, in part, to be due to the genetic and functional heterogeneity of AML. ~13 Tier 1 mutations occur per patient sample arrayed in 2-5 clones (CGARN, N Engl J Med, 2013). Not all AML cell populations may be equally chemosensitive; for example, leukemia-propagating leukemic stem cells (LSC) are more chemoresistant. (Ishikawa et al., Nat Biotechnol, 2007). Additionally, the impact of genetic heterogeneity on LSC function is unclear. In ~ 70% of primary human AML with >2% CD34+ cells, LSCs exist within both CD34+CD38- and CD34+CD38+ compartments (Taussig et al., Blood, 2008), and have progenitor-like transcriptional programmes (Goardon et al., Cancer Cell, 2011). ~30% of AML with <2% CD34+ cells (CD34- AML) are genetically distinct, enriched for mutations in NPM1 and co-associated mutations (FLT3, IDH1/2, TET2, and DNMT3A). Here, LSC activity has been detected in both CD34+ and CD34- compartments (Taussig et al., Blood, 2010, Martelli et al., Blood, 2010, Sarry et al., J Clin Invest, 2011). Questions remain about CD34- AML LSC populations: (i) What is the relationship between CD34- and CD34+ LSCs? (ii) What are the nearest counterpart normal haemopoietic cells to LSCs at a global transcriptional level? (iii) What is the impact of genetic heterogeneity on LSC function? Do all clones have equal LSC potential? Of a sequential cohort of 49 CD34- samples, 55% of 38 samples karyotyped had normal karyotype. 29/49 (59%) had mutated NPM1. Co-occurring mutations were FLT3 (54%), IDH1/2 (54%) and DNMT3A (26%). 11/28 samples with sufficient cells engrafted AML confirmed on mutation analysis. In 8/11 samples (7 were NPM1-mutated) sufficient available cells were available for detailed studies. LSC populations in serial transplant assays were present in both minor CD34+ and CD34-; CD34- populations were CD117+ and CD244+ or CD244-. Limit dilution analysis showed similar LSC frequencies in CD34+ and CD34- fractions from the same patient. Unexpectedly, there was no hierarchy with respect to CD34 expression and CD34 expression did not mark functionally distinct LSC populations. RNA-sequencing of 5 CD34+ and 14 CD34- LSC populations from 8 patient samples showed only 42 differentially protein coding genes out of 15539 expressed genes. We used ANOVA analysis to identify 300 top-ranking differentially expressed genes between normal stem/progenitor and myeloid and erythroid precursor populations. Using this signature, principal component analysis showed CD34- AML LSCs (CD34+ and CD34-) are closest to CD34-CD117+CD244+ populations that are promyelocytes have no D14 progenitor function in CFC assays and express late granulocytic macrophage (GM) genes. CD244 separates normal CD34-CD117+ populations into GM (CD244+) from erythroid (CD244-) precursors so allowing greater precision in mapping CD34-AML LSC to normal GM counterparts. CD34-AML LCS were not only enriched for a GM precursor signature, but also for a transcriptional signature seen in normal HSC. CD34- AML LSC expressed 63/100 transcription factor (TF) genes expressed in HSC including HOX and HOX co-factors. Interestingly, LSCs in CD34- AML had a distinct RNA-Seq profile from CD34+ progenitor-like LSCs populations. To explore genetic and functional heterogeneity of LSC populations, bulk and single cell genotyping of LSC populations revealed: (i) branching subclonal structures; with up to 5 genetically distinct LSC clones/patient; (ii) intermediate genotypes where the order of mutation acquisition was identified; (iii) some but not all patient LSC clones could be propagated in mice suggesting that current immunodeficient murine strains do not accurately model human AML. Thus, studies of LSC function have to combine both studies in mice and of primary human samples. In summary, within CD34- AML there are multiple, non-hierarchically arranged LSC populations with transcriptional programmes most closely related to normal CD34- GM precursors. Unlike these normal mature cells, LSCs also express HSC transcriptional signatures. Functional and genetic analysis of single cells and populations from patient LSC, non-LSC compartments and of xenografts reveals clonal structure, order of acquisition of mutations, how subclones are distributed in different immunophenotypic populations, some with different functional properties and, differences in subclonal representation between patients and xenografts. Disclosures No relevant conflicts of interest to declare.

Purpose Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune–mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract. Methods Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn’s disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay. Results Novel germline loss-of-function variants in SOCS1 were identified in both p...

Supplementary Figure 1. Anti-CD3 stimulation of primary human T-ALLs. Supplementary Figure 2. TCR stimulation by in vivo administration of agonistic monoclonal antibody in a preventive setting inhibits human TCR+ T-ALL development. Supplementary Figure 3. TCR signaling is essential to the anti-leukemic effect of OKT3. Supplementary Table 1. Immunophenotypic and oncogenic characteristics of T-ALL samples.

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a RHO-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels conco...

Les signaux issus du microenvironnement jouent un role determinant dans l'hematopoiese, et leur alteration est retrouvee de maniere recurrente dans les hemopathies. Ce travail de these a consiste a analyser les recepteurs de surface et leur signalisation dans l’hematopoiese normale et pathologique, afin d'identifier des recepteurs susceptibles de presenter un interet diagnostique, pronostique ou therapeutique. Dans une premiere partie, la lymphopoiese T normale et pathologique est abordee au travers de l'etude de la signalisation FLT3 et TGFbeta. La signalisation fonctionnelle, ectopique et oncogenique de FLT3 dans les LAL-T est rapportee, de meme qu'un mecanisme de redondance entre recepteurs cytokiniques, suggerant l'interet de l'inhibition multicible dans cette pathologie. Le mecanisme de regulation post-traductionnelle de la proteine TAL1 dans les LAL-T est rapportee. L'etude est completee par une cartographie phenotypique extensive de la differenciat...

*° contributed equally to this work. Introduction: Systemic Mastocytosis (SM) is a heterogeneous disorder characterized by mast cells (MCs) accumulation in various tissues and associated with KIT mutations (KIT D816V) in more than 90% of the cases. It includes indolent (ISM) and advanced diseases (advSM), which are associated with additional molecular abnormalities. For advSM, recent clinical studies have shown that Midostaurin, a kinase inhibitor of WT and mutant KIT, induces high rate of responses associated with significant improvement of prognosis. However, complete responses are infrequent and relapses occur in a significant proportion of patients. Therefore, combination therapies are needed to increase overall response rate and prevent relapses. Venetoclax is a selective orally bioavailable BCL-2 inhibitor that induces cell death and is currently used for treatment of various lymphoid and myeloid malignancies. In an attempt to identify novel diagnostic and prognostic markers and potentially new therapeutic targets for mastocytosis, bone marrow sections of patients with different categories of mastocytosis were analyzed by IHC using anti-BCL-2 antibodies. BH-3 profiling was used to assess BH-3 proteins dependency, and sensitivity to Venetoclax alone or in combination of Midostaurin. Methods: Thirty-three adult patients were included in this preliminary study. According to the WHO classification, patients were classified as having ISM (n=10), Smoldering SM (SSM n=1), advSM (n=16, including SM-AHN (n=9), MC leukemia (MCL n=4), MC sarcoma (MCS n=2)). Most patients were KIT D816V (n=30; 90.9%); two MCL and one MCS exhibited extracellular and juxtamembrane mutations, respectively. Among these patients, 9 were treated with Midostaurin as first line therapy. Formalin fixed bone marrow sections were performed at diagnosis and during follow up. Mast cells were identified by Giemsa staining and as CD117 and tryptase positive cells. BCL-2 staining was performed by immunohistochemistry in formalin paraffin embedded fixed section. BCL-2 staining was considered as positive (>5%), heterogeneous (partial staining) or homogeneous (>80% positive cells), of high or low intensity (> or = or < to residual T cells). BH3 profiling was performed in ROSA KIT WT and ROSA KIT D816V using Cytochrome C upon exposure to distinct BH3 peptides/mimetics. Results: In ISM, BCL-2 staining was negative (n= 2/10) or when positive only in rare MCs (n=8/10), with low intensity. In contrast, all advSM cases were positive (16/16) with high (13/16), and homogeneous (6/16) staining. In MCL and MCS, BCL-2 staining was always positive with a homogeneous and high staining. In patients treated with Midostaurin, BCL-2 staining was performed before and three months after treatment initiation. Although MCs infiltration was reduced at least by 50% in all cases, number of BCL-2 positive cells and intensity of staining remain unchanged. In vitro, flow cytometry analysis showed that both MCL-like cell lines (ROSA KIT WT and ROSA KIT D816V) expressed BCL-2, MCL-1 and BCL-XL proteins. When treated with Midostaurin (200nM) for 48 hours, expression of BCL-XL and MCL-1 significantly decreased in MC lines especially the one with KIT D816V mutation. Interestingly, BCL-2 expression remained unchanged upon Midostaurin treatment, which was consistent with in vivo observations. Dynamic profiling performed in ROSA cell lines revealed that priming by midostaurin dramatically enhanced apoptotic dependencies to BCL-2 and other BH-3 proteins (>20% of apoptosis), especially in ROSA KIT D816V (figure). Conclusion: High expression of BCL-2 is associated with advSM and may participate to the pathogenesis of the disease, to its resistance to conventional chemotherapies and to partial resistance to Midostaurin. Consistent with its effect in reducing MCL-1 and BCL-XL expression, Midostaurin restored apoptotic dependency to BCL2 in human MCL-like cells, thereby suggesting that midostaurin could sensitize mast cell tumor to venetoclax. Our results provide thus a rationale to use a combination of Midostaurin and Venetoclax to treat AdvSM patients. Figure Disclosures Dubreuil: AB Science: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hermine:AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. OffLabel Disclosure: Venetoclax preclinical studioes on mastocytosis

Lack of progress in curing AML is likely, in part, to be due to the genetic and functional heterogeneity of AML. ~13 Tier 1 mutations occur per patient sample arrayed in 2-5 clones (CGARN, N Engl J Med, 2013). Not all AML cell populations may be equally chemosensitive; for example, leukemia-propagating leukemic stem cells (LSC) are more chemoresistant. (Ishikawa et al., Nat Biotechnol, 2007). Additionally, the impact of genetic heterogeneity on LSC function is unclear. In ~ 70% of primary human AML with >2% CD34+ cells, LSCs exist within both CD34+CD38- and CD34+CD38+ compartments (Taussig et al., Blood, 2008), and have progenitor-like transcriptional programmes (Goardon et al., Cancer Cell, 2011). ~30% of AML with <2% CD34+ cells (CD34- AML) are genetically distinct, enriched for mutations in NPM1 and co-associated mutations (FLT3, IDH1/2, TET2, and DNMT3A). Here, LSC activity has been detected in both CD34+ and CD34- compartments (Taussig et al., Blood, 2010, Martelli et al....

Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide towards the relevant classification panel (T-cell acute lymphoblastic leukemia (T-ALL), B-cell precursor (BCP)-ALL, and/or acute myeloid leukemia (AML)) and final diagnosis. Now we built a reference database with 656 typical AL samples (145 T-ALL, 377 BCP-ALL, 134 AML), processed and analyzed via standardized protocols. Using principal component analysis (PCA)-based plots and automated classification algorithms for direct comparison of single-cells from individual patients against the database, another 783 cases were subsequently evaluated. Depending on the database-guided results, patients were categorized as: i) typical T, B, or Myeloid without or; ii) with a transitional component to another lineage; iii) atypical; or iv) mixed-lineage. Using this automated algorithm, in 781/783 cases (99.7%) the right panel was selected, and dat...

Neonates and children with Down Syndrome (DS), with constitutional Trisomy 21 (T21), have a 150-fold increased risk of developing Myeloid Leukaemia (ML-DS), with differentiation arrest of immature megakaryocyte-erythroid cells. Virtually all ML-DS patients have in utero-acquired somatic mutations in the gene encoding the megakaryocyte-erythroid transcription factor GATA1 leading to the production of an 84 amino acid N-terminal truncated form of the GATA1 protein (GATA1s). We, and others, have previously shown that this N-terminal domain is necessary to prevent excessive megakaryocytic proliferation. However, the mechanisms by which GATA1, but not GATA1s, restrains megakaryocyte proliferation are unclear. We generated knock-in murine ES cell models expressing biotinylated forms of either full length GATA1 or GATA1s protein. We established a large scale in vitro differentiation assay to study embryonic-fetal megakaryocyte differentiation to define the normal megakaryocytic differentiation pathway in GATA1-expressing cells. ES cells were differentiated into embryoid bodies (EBs), which were disaggregated after 6 days and CD41+c-kit+ cells were cultured on OP9 feeder layers with TPO, IL6 and IL11. Detailed examination of the differentiation kinetics including FACS-sorting of specific populations followed by re-culture or Biomark qRT-PCR analysis, showed complex differentiation pathways as wild type cells differentiated into both megakaryocyte and non-megakaryocyte (both erythroid and myeloid) fates. By contrast, GATA1s-expressing cells almost exclusively differentiated into megakaryocyte lineage. Furthermore, as immature CD41+ haemopoietic cells differentiate into the megakaryocyte lineage, they lose c-kit expression and CD41 expression increases. In the GATA1s-expressing cells compared to GATA1-expressing cells, there is a significant accumulation (5 to 10-fold) of a specific immature megakaryocyte CD41++c-kit+ population, partially blocked in differentiation. Cell cycle analysis showed an increase in cells in S-phase specifically in this population in GATA1s-expressing cells (44% compared to 27% in normal cells) together with a decrease in apoptosis (5% compared to 11% in normal cells). To determine the relevance of these findings in vivo , corresponding mouse models were generated and experiments on yolk sacs isolated at different stages of development are ongoing. Taken together, these data suggest that our in vitro murine ES cell differentiation model is a relevant tool to dissect the molecular mechanisms underlying GATA1s function in abnormal megakaryocytic differentiation and they are likely to provide insight into general mechanisms of how altered function of a critical lineage-affiliated transcription factor can lead to multiple changes in progenitor cell cycle and differentiation. Disclosures Vyas: Celgene Corporation: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau.

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and ...

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neopla...

Introduction Aggressive B-cell lymphomas are heterogeneous in their clinical course and biological characteristics. They include diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), high grade-B-cell lymphoma with double/triple-hit or NOS (HGBL), primary mediastinal B-cell lymphoma (PMBL). In order to better differentiate these entities, the WHO classification recommends using immunohistochemistry (IHC), FISH, targeted sequencing and gene expression profiles (GEP). However, these techniques are most often performed retrospectively in clinical trials, which is not representative of real life. In order to use these information to improve the current standard of treatment with targeted therapies adapted to lymphoma biology, we have set up a national network on behalf of the LYSA called RT3 (for Real-time tailored therapy) to demonstrate that we are able to comprehensively characterize aggressive B cell lymphomas in a clinically relevant timeline. Materials and methods Pat...

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-ye...

A key challenge in the clinical proteomics of cancer is the identification of biomarkers that would enable early detection, diagnosis and monitoring of disease progression to improve long-term survival of patients. Recent advances in proteomic instrumentation and computational methodologies offer a unique chance to rapidly identify these new candidate markers or pattern of markers. The combination of retentate affinity chromatography and mass spectrometry is one of the most interesting new approaches for cancer diagnostics using proteomic profiling. This review presents two technologies in this field, surface-enhanced laser desorption/ionization time-of-flight and Clinprot, and aims to summarize the results of studies obtained with the first of them for the early diagnosis of human cancer. Despite promising results, the use of the proteomic profiling as a diagnostic tool brought some controversies and technical problems, and still requires some efforts to be standardized and validated.

Background Enteropathy-associated T-cell lymphoma (EATL), previously designated type 1 EATL, is a neoplasm of intraepithelial T cells that occurs in individuals with celiac disease (CD). It is a rare lymphoma, accounting for approximately 3% of all peripheral T-cell lymphomas (PTCLs). EATL may be preceded by refractory CD (RCD), defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy despite a strict gluten-free diet for more than 12 months. Currently, RCD is categorized into 2 types, based on immunophenotypic and molecular criteria. In RCD-II, intraepithelial lymphocytes (IELs) have an aberrant phenotype and a clonal TCR gene rearrangement. RCD-II is considered a low-grade lymphoma of intraepithelial T cells, with a high risk of transformation into EATL. CD or RCD may be diagnosed prior to or concomitant with EATL. EATL has a poor prognosis due to perforation or obstruction of the bowel, sepsis, malnutrition and treatment resistance, with 2-year ...

Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P = .001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, K...