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In 2022, two new classifications of myeloid neoplasms and acute leukemias were published: the 5th edition WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC). As with prior classifications, the WHO-HAEM5 and ICC made updates to the prior classification (revised 4th edition WHO Classification, WHO-HAEM4R) based on a consensus of groups of experts, who examined new evidence. Both WHO-HAEM5 and ICC introduced several new disease entities that are based predominantly on genetic features, superseding prior morphologic definitions. While it is encouraging that two groups independently came to similar conclusions in updating the classification of myeloid neoplasms and acute leukemias, there are several divergences in how WHO-HAEM5 and ICC define specific entities as well as differences in nomenclature of certain diseases. In this review, we highlight the similarities and differences between the WHO-HAEM5 and ICC handling of myeloid neoplasms and acute leukemias and present a practical approach to diagnosing and classifying these diseases in this current era of two divergent classification guidelines.
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Leucemia Mieloide Aguda , Organização Mundial da Saúde , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/diagnóstico , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologiaRESUMO
Not available.
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Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs.
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AIMS: B lymphoblastic leukaemia/lymphoma (B-ALL) is thought to originate from Pro/Pre-B cells and the genetic aberrations largely reside in lymphoid-committed cells. A recent study demonstrated that a proportion of paediatric B-ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)-like biology in this peculiar subset of B-ALL, although it is not entirely clear if the CD19-negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion-driven B-ALLs. METHODS AND RESULTS: In this study we investigated a cohort of KMT2A-rearranged B-ALL patients with a comparison to BCR::ABL1-rearranged B-ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A-rearranged B-ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A-rearranged B-ALL with multilineage involvement. CONCLUSIONS: In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.
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Histona-Lisina N-Metiltransferase , Proteína de Leucina Linfoide-Mieloide , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Histona-Lisina N-Metiltransferase/genética , Feminino , Criança , Masculino , Pré-Escolar , Adolescente , Proteínas de Fusão bcr-abl/genética , Adulto , Hibridização in Situ Fluorescente , Lactente , Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adulto Jovem , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , IdosoRESUMO
ABSTRACT: Although significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in patients with lymphoma (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or natural killer-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harboring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.
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Linfo-Histiocitose Hemofagocítica , Mutação , Receptor fas , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/etiologia , Receptor fas/genética , Feminino , Masculino , Pessoa de Meia-Idade , Linfoma de Células T/genética , Linfoma de Células T/complicações , Adulto , Transdução de Sinais , Células Matadoras Naturais/metabolismo , Idoso , Predisposição Genética para DoençaAssuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Mutação , Fosfoproteínas , Fatores de Processamento de RNA , Trombocitose , Humanos , Fatores de Processamento de RNA/genética , Trombocitose/genética , Trombocitose/diagnóstico , Fosfoproteínas/genética , Cromossomos Humanos Par 5/genética , Anemia Sideroblástica/genética , Anemia Sideroblástica/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
Introduction: In vivo studies of cancer biology and assessment of therapeutic efficacy are critical to advancing cancer research and ultimately improving patient outcomes. Murine cancer models have proven to be an invaluable tool in pre-clinical studies. In this context, multi-parameter flow cytometry is a powerful method for elucidating the profile of immune cells within the tumor microenvironment and/or play a role in hematological diseases. However, designing an appropriate multi-parameter panel to comprehensively profile the increasing diversity of immune cells across different murine tissues can be extremely challenging. Methods: To address this issue, we designed a panel with 13 fixed markers that define the major immune populations -referred to as the backbone panel- that can be profiled in different tissues but with the option to incorporate up to seven additional fluorochromes, including any marker specific to the study in question. Results: This backbone panel maintains its resolution across different spectral flow cytometers and organs, both hematopoietic and non-hematopoietic, as well as tumors with complex immune microenvironments. Discussion: Having a robust backbone that can be easily customized with pre-validated drop-in fluorochromes saves time and resources and brings consistency and standardization, making it a versatile solution for immuno-oncology researchers. In addition, the approach presented here can serve as a guide to develop similar types of customizable backbone panels for different research questions requiring high-parameter flow cytometry panels.
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Corantes Fluorescentes , Neoplasias , Animais , Camundongos , Citometria de Fluxo/métodos , Neoplasias/metabolismo , Microambiente TumoralRESUMO
This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms, and genetic tumor syndromes of the 5th edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The diagnostic, clinicopathologic, cytogenetic, and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the World Health Organization classification of hematolymphoid neoplasms are highlighted.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Organização Mundial da Saúde , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Eosinofilia/patologia , Eosinofilia/genética , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/classificação , FenótipoRESUMO
Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.
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Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo. SIGNIFICANCE: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695.
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Janus Quinase 2 , Transtornos Mieloproliferativos , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transdução de SinaisRESUMO
Lemon essential oil (LEO) is a common natural antibacterial substance, and encapsulating LEO into nanoemulsions (NEs) can improve their stability and broaden its application. Our study aimed to investigate the bacterial inhibitory effect of LEO-NEs against Escherichia coli (E. coli). Results showed that the minimum inhibitory concentration (MIC) of LEO-NEs was 6.25 mg/mL, and the time-kill curve showed that E. coli were significantly killed by LEO-NEs after 5 h of treatment at 1MIC. Flow-cytometry analysis showed that LEO-NEs adversely affected the cell-membrane depolarisation, cell-membrane integrity, and efflux pump function of E. coli. Confocal laser scanning microscopy demonstrated that 8MIC of LEO-NEs induced changes in the cell-membrane permeability and cell-wall integrity of E. coli. Proteomic results suggested that the mode of action LEO-NEs against E. coli was to enhance bacterial chemotaxis and significantly inhibit ribosomal assembly. They may also affect butyric acid, ascorbic acid and aldehyde metabolism, and sulphur-relay system pathways. In conclusion, LEO-NEs had potential application as a natural antibacterial agent for the control of E. coli in the food industry.
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Escherichia coli , Óleos Voláteis , Proteômica , Antibacterianos/farmacologia , Óleos Voláteis/farmacologia , Membrana Celular , BactériasRESUMO
ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.
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Hematopoiese Clonal , Neoplasias Hematológicas , Humanos , Idoso , Hematopoese/genética , Mutação , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , GenótipoRESUMO
Mixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (AML-MP) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MRC and t-AML with MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML-MRC/t-AML without MP. Both AML cohorts with and without MP shared similar clinical features including adverse outcomes but were different from MPAL. The genomic landscape of AML-MP overlaps with AML without MP but differs from MPAL. AML-MP harbors more frequent RUNX1 mutations than AML without MP and MPAL. RUNX1 mutations did not impact the survival of patients with MPAL. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML-MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML. Key points: AML-MP clinically and biologically resembles AML but differs from MPAL. AML-MP shows RUNX1 mutations, stemness signatures and limited lymphoid lineage plasticity.
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Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.
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Neoplasias Hematológicas , Neoplasias , Humanos , Neoplasias/genética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Mutação , Sequenciamento de Nucleotídeos em Larga Escala , DNARESUMO
Measurable residual disease (MRD), defined as the population of cancer cells that persist following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones, and normal precursors remains a challenge with current MRD tools. Here, we developed a single-cell MRD (scMRD) assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated single-cell DNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture, and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/preleukemic and leukemic cells surviving acute myeloid leukemia therapy.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Bioensaio , Citometria de Fluxo , Genótipo , ImunofenotipagemRESUMO
Ototoxic drugs such as aminoglycoside antibiotics and cisplatin (CDDP) can cause sensorineural hearing loss (SNHL), which is closely related to oxidative stress and the acidification of the inner ear microenvironment. Effective treatment of SNHL often requires multifaceted approach due to the complex pathology, and drug combination therapy is expected to be at the forefront of modern hearing loss treatment. Here, space-station-like composite nanoparticles (CCC@mPP NPs) with pH/oxidation dual responsiveness and multidrug simultaneous delivery capability were constructed and then loaded with various drugs including panax notoginseng saponins (PNS), tanshinone IIA (TSIIA), and ammonia borane (AB) to provide robust protection against SNHL. Molecular dynamics simulation revealed that carboxymethyl chitosan/calcium carbonate-chitosan (CCC) NPs and monomethoxy poly(ethylene glycol)-PLGA (mPP) NPs can rendezvous and dock primarily by hydrogen bonding, and electrostatic forces may be involved. Moreover, CCC@mPP NPs crossed the round window membrane (RWM) and entered the inner ear through endocytosis and paracellular pathway. The docking state was basically maintained during this process, which created favorable conditions for multidrug delivery. This nanosystem was highly sensitive to pH and reactive oxygen species (ROS) changes, as evidenced by the restricted release of payload at alkaline condition (pH 7.4) without ROS, while significantly promoting the release in acidic condition (pH 5.0 and 6.0) with ROS. TSIIA/PNS/AB-loaded CCC@mPP NPs almost completely preserved the hair cells and remained the hearing threshold shift within normal limits in aminoglycoside- or CDDP-treated guinea pigs. Further experiments demonstrated that the protective mechanisms of TSIIA/PNS/AB-loaded CCC@mPP NPs involved direct and indirect scavenging of excessive ROS, and reduced release of pro-inflammatory cytokines. Both in vitro and in vivo experiments showed the high biocompatibility of the composite NPs, even after long-term administration. Collectively, this work suggests that composite NPs is an ideal multi-drug-delivery vehicle and open new avenues for inner ear disease therapies.
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Quitosana , Perda Auditiva Neurossensorial , Nanopartículas , Animais , Cobaias , Ácido Láctico/química , Quitosana/química , Hidrogênio , Medicina Tradicional Chinesa , Espécies Reativas de Oxigênio , Perda Auditiva Neurossensorial/tratamento farmacológico , Cisplatino , Nanopartículas/química , AminoglicosídeosRESUMO
The optimal induction strategy for mixed phenotype acute leukemia (MPAL) is unknown, though retrospective data has shown improved remission rates and overall survival with acute lymphoblastic leukemia (ALL)-based regimens. At Memorial Sloan Kettering Cancer Center (MSKCC), the most utilized induction regimen for MPAL is high dose cytarabine plus mitoxantrone ("ALL-2"), though outcomes with this regimen are not well described. In this study, outcomes to first-line induction chemotherapy in 24 patients at MSKCC with MPAL classified by 2016 World Health Organization criteria are reported. The overall response rate was 94 % (16 of 17) in patients receiving ALL-2, including 86 % (6 of 7) in patients with extramedullary disease. Thirteen patients who received ALL-2 induction proceeded to allogeneic hematopoietic cell transplant (allo-HCT). The most common toxicity associated with ALL-2 was febrile neutropenia, documented in 12 patients. With a median follow-up of 37 months, median overall survival was not reached in the ALL-2 cohort, and 3-year overall survival was 62 %. In multivariate analysis, age ≥ 60 years and MPAL with isolated extramedullary disease were associated with significantly worse overall survival (P = .009 and P = .01, respectively). These results support further prospective investigation of ALL-2 as a front-line induction regimen for adults with MPAL.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Mitoxantrona , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Aguda , Citarabina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fenótipo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMO
OBJECTIVES: To summarize the conclusions of the 2021 Society for Hematopathology/European Association for Haematopathology workshop regarding transformations of marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). METHODS: Nineteen cases were submitted to this portion of the workshop. Additional studies were performed in cases with sufficient material. RESULTS: Cases included splenic MZL (n = 4), splenic diffuse red pulp small B-cell lymphoma (n = 2), nodal MZL (n = 4), extranodal MZL (n = 1), and LPL (n = 8). The most common transformation was to diffuse large B-cell lymphoma (DLBCL), but others included classic Hodgkin lymphoma, high-grade B-cell lymphomas with MYC and BCL6 rearrangements, plasmablastic lymphoma, and plasma cell leukemia. Two splenic MZLs with transformation to DLBCL contained t(14;19)(q32;q13.3) IGH::BCL3 rearrangements in both samples. Paired sequencing studies in 5 MZLs with transformation to clonally related DLBCL identified a variety of mutations and gene fusions at the time of transformation, including CARD11, IGH::MYC, NOTCH2, P2RY8, TBLX1X1, and IGH::CD274. CONCLUSIONS: Marginal zone lymphoma and LPL may undergo a variety of transformation events, most commonly to DLBCL, which is usually, although not always, directly clonally related to the underlying low-grade lymphoma. Multiparameter analysis including broad-based sequencing studies can assist in the diagnosis and classification of these uncommon cases.
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OBJECTIVES: Sessions 8 and 9 of the 2021 Society for Hematopathology and the European Association for Haematopathology Workshop aimed to collect examples of transdifferentiation, lineage infidelity, progression, and transformation in precursor and mature T/natural killer (NK)-cell neoplasms. METHODS: Twenty-eight cases were submitted and analyzed, with whole-exome sequencing and genome-wide RNA expression analysis performed in a subset of the cases. RESULTS: In session 8, 7 T-lymphoblastic lymphoma/leukemia cases were received that showed transdifferentiation to clonally related mature myeloid hematopoietic neoplasms, including 6 histiocytic/dendritic cell lineage neoplasms and a mast cell sarcoma. Session 9 included 21 mature T-cell neoplasms that were grouped into 3 themes. The first one addressed phenotypic infidelity in mature T-cell lymphomas (TCLs) and included 8 TCLs expressing aberrant antigens, mimicking classic Hodgkin and non-Hodgkin B-cell lymphomas. The second theme addressed disease progression in TCL and included 5 cutaneous T-cell lymphoproliferative disorders and 2 T-cell large granular lymphocyte proliferations with subsequent progression to systemic TCL. The third theme included 6 patients with TCL with T-follicular helper phenotype, mainly angioimmunoblastic T-cell lymphoma, with concurrent/subsequent clonal hematopoiesis or myeloid neoplasms and/or subsequent/concomitant diffuse large B-cell lymphoma. CONCLUSIONS: This cohort of cases allowed us to illustrate, discuss, and review current concepts of transdifferentiation, aberrant antigen expression, and progression in various T/NK-cell neoplasms.