Complex heatmap visualization

iMeta, Год журнала: 2022, Номер 1(3)

Опубликована: Авг. 1, 2022

Abstract Heatmap is a widely used statistical visualization method on matrix‐like data to reveal similar patterns shared by subsets of rows and columns. In the R programming language, there are many packages that make heatmaps. Among them, ComplexHeatmap package provides richest toolset for constructing highly customizable can easily establish connections between multisource information automatically concatenating adjusting list heatmaps as well complex annotations, which makes it applied in analysis fields, especially bioinformatics, find hidden structures data. this article, we give comprehensive introduction current state , including its modular design, rich functionalities, broad applications.

Язык: Английский

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Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Cancer Discovery, Год журнала: 2021, Номер 12(2), С. 388 - 401

Опубликована: Ноя. 17, 2021

Abstract We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, application in clinical treatment decisions. Actionable drugs were found 97% AML, the recommendations clinically implemented 37 relapsed or refractory patients. report 59% objective response rate individually tailored therapies, including 13 complete responses, as well bridging five AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled identification drug biomarkers, such association IL15 overexpression resistance FLT3 inhibitors. Integration molecular large-scale many will enable continuous improvement FPMTB recommendations, providing paradigm individualized implementation cancer medicine. Significance: Oncogenomics can guide decisions, but often are neither actionable nor predictive. Functional testing contributes significant additional, therapeutic insights individual AML. Such be four days, enabling rapid translation through FPMTB. See related commentary by Letai, p. 290. This article is highlighted In Issue feature, 275

Язык: Английский

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Single-cell characterization of anti–LAG-3 and anti–PD-1 combination treatment in patients with melanoma

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(6)

Опубликована: Янв. 31, 2023

BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 anti-programmed death 1 [anti-LAG-3+anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on immune system is unknown.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated anti-LAG-3+anti-PD-1 in phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαβ-Seq) combined other multiomics profiling.ResultsThe highest LAG3 expression was noted NK cells, Tregs, CD8+ these populations underwent most significant changes during treatment. Adaptive cells were enriched responders profound transcriptomic therapy, resulting an active phenotype. LAG3+ Tregs expanded, based transcriptome profile, became metabolically silent Last, higher baseline TCR clonality observed responding patients, their expanding clones gained more cytotoxic NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 effects addition to cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer Foundation Finland, Sigrid Juselius Foundation, Signe Ane Gyllenberg Relander State funding university-level health research Helsinki Institute of Life Sciences Fellow grant, Academy Finland (grant numbers 314442, 311081, 335432, 335436), investigator-initiated grant BMS.

Язык: Английский

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Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas

Immunity, Год журнала: 2020, Номер 54(1), С. 116 - 131.e10

Опубликована: Дек. 2, 2020

Язык: Английский

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HLA informs risk predictions after haploidentical stem cell transplantation with posttransplantation cyclophosphamide

Blood, Год журнала: 2021, Номер 139(10), С. 1452 - 1468

Опубликована: Ноя. 1, 2021

Язык: Английский

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Current status and future perspectives in targeted therapy of NPM1-mutated AML

Leukemia, Год журнала: 2022, Номер 36(10), С. 2351 - 2367

Опубликована: Авг. 25, 2022

Abstract Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis export, histone assembly, maintenance genomic stability response to nucleolar stress. NPM1 mutations are most common genetic alteration acute myeloid leukemia (AML), detected about 30–35% adult AML more than 50% with normal karyotype. Because its peculiar molecular clinico-pathological features, aberrant cytoplasmic dislocation mutant wild-type proteins, lack involvement driving clonal hematopoiesis, mutual exclusion recurrent cytogenetic abnormalities, association unique gene expression micro-RNA profiles high at relapse, -mutated regarded as distinct entity World Health Organization (WHO) classification hematopoietic malignancies. Starting from structure functions NPM1, we provide an overview potential targeted therapies against discuss strategies aimed interfering oligomerization (compound NSC348884) abnormal traffic (avrainvillamide, XPO1 inhibitors) well inducing selective NPM1-mutant degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) targeting integrity (actinomycin D). We also current therapeutic results obtained BCL-2 inhibitor venetoclax preliminary clinical using menin inhibitors HOX/MEIS1 expression. Finally, review various immunotherapeutic approaches AML, immune check-point inhibitors, CAR TCR T-cell-based neoantigens created by mutations.

Язык: Английский

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Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood Cancer Discovery, Год журнала: 2021, Номер 2(6), С. 616 - 629

Опубликована: Сен. 10, 2021

Abstract Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses relapsed/refractory (R/R) AML. Overall responders could receive maintenance up 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), median survival (OS) were 46%, 38%, 11.1 months, respectively. Patients with refractory/early relapse those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 11.3 respectively). Grade ≥3 immune-related adverse events rare (14%) self-limiting. who achieved CRc higher frequency progenitor exhausted CD8+ T cells expressing TCF-1 bone marrow prior treatment. A multifaceted correlative approach genomic, transcriptomic, immunophenotypic profiling offers insights molecular correlates resistance pembrolizumab. Significance: Immune-checkpoint blockade was tolerable feasible after R/R AML, activity, particularly refractory AML regimen. Further other immune-checkpoint strategies cytotoxic chemotherapy is warranted See related commentary Wei et al., p. 551. This article highlighted In Issue feature, 549

Язык: Английский

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Immune dysfunction signatures predict outcomes and define checkpoint blockade–unresponsive microenvironments in acute myeloid leukemia

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(21)

Опубликована: Сен. 13, 2022

Background. Immune exhaustion and senescence are dominant dysfunctional states of effector T cells major hurdles for the success cancer immunotherapy. In current study, we characterized how acute myeloid leukemia (AML) promotes generation senescent-like CD8+ whether they have prognostic relevance.

Язык: Английский

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Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia

Blood, Год журнала: 2022, Номер 141(13), С. 1610 - 1625

Опубликована: Дек. 12, 2022

Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure leukemia, myelodysplastic syndrome features, and acute megakaryoblastic leukemia (FAB M7) are characterized by poor prognosis limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that myeloid (AML) cells depend on antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo testing, genetic perturbation, transcriptomic profiling. High-throughput screening >500 compounds identified BCL-XL-selective inhibitor A-1331852 navitoclax as highly effective against erythroid/megakaryoblastic cell lines. In contrast, AML subtypes were resistant to BCL-2 venetoclax, which is used clinically in AML. Consistently, genome-scale CRISPR-Cas9 RNAi data demonstrated striking essentiality BCL-XL-encoding BCL2L1 but not BCL2 MCL1, for survival Single-cell bulk transcriptomics patient samples leukemias high expression compared other hematological malignancies, where MCL1 more prominent. BCL-XL inhibition effectively killed blasts from patients reduced tumor burden a mouse erythroleukemia xenograft model. Combining JAK ruxolitinib showed synergistic durable responses Our results suggest targeting potential therapy option highlight an subgroup potentially venetoclax-based treatments.

Язык: Английский

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Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities

Journal for ImmunoTherapy of Cancer, Год журнала: 2022, Номер 10(7), С. e004892 - e004892

Опубликована: Июль 1, 2022

Background Immune microenvironment is well recognized as a critical regulator across cancer types, despite its complex roles in different disease conditions. Intrahepatic cholangiocarcinoma (iCCA) characterized by tumor-reactive milieu, emphasizing deep insight into immunogenomic profile to provide prognostic and therapeutic implications. Methods We performed genomic, transcriptomic, proteomic characterization of 255 paired iCCA adjacent liver tissues. validated our findings through H&E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10), vitro functional studies, vivo transposon-based mouse models. Results Integrated multimodule data identified three immune subgroups with distinct clinical, genetic, molecular features, designated IG1 (immune-suppressive, 25.1%), IG2 (immune-exclusion, 42.7%), IG3 (immune-activated, 32.2%). was excessive infiltration neutrophils immature dendritic cells (DCs). The hallmark the relatively higher tumor-proliferative activity tumor purity. exhibited an enrichment adaptive cells, natural killer activated DCs. These were significantly associated prognosis two independent cohorts. Tumors KRAS mutations enriched myeloid inflammation-dominated immunosuppression. Although mutation burden IG2, loss heterozygosity human leucocyte antigen defects presentation undermined recognition neoantigens, contributing immune-exclusion behavior. Pathological analysis confirmed that tumor-infiltrating lymphocytes tertiary lymphoid structures both predominant IG3. Hepatitis B virus (HBV)-related samples tended be under-represented IG1, scRNA-seq analyses implied HBV infection indeed alleviated inflammation reinvigorated antitumor immunity. Conclusions Our study elucidates traits are intrinsically heterogeneous among patients, posing great challenge opportunity for application personalized immunotherapy.

Язык: Английский

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