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Several editions of the World Health Organization (WHO) classifications of lympho-hemopoietic neoplasms in 2001, 2008 and 2017 served as the international standard for diagnosis. Since the 4th WHO edition, here referred as WHO-HAEM4, significant clinico-pathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining diagnostic criteria of several diseases, to upgrade entities previously defined as provisional and to identify new entities. This process has resulted in two recent classifying proposals of lymphoid neoplasms, the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with focus on mature B-cell neoplasms. The main aim is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of lymphomas.

Dactinomycin is an old drug with activity in some childhood cancers; it acts as an inhibitor of RNA polymerase I. Its activity in acute myeloid leukemia has not been thoroughly examined. However, it has induced remissions in some patients with treatment-refractory disease. To the Editor: NPM1 -mutated acute myeloid leukemia (AML) is a distinct leukemia entity that accounts for one third of cases of AML in adults. 1 NPM1 is a crucial protein for normal nucleolar integrity and function. We hypothesized that the nucleolus of NPM1 -mutated AML cells might be vulnerable to drugs that trigger a nucleolar stress response because it contains a low level of nonmutant NPM1 2 (owing to haploinsufficiency and cytoplasmic retention of nonmutant NPM1 by the NPM1 mutant 1 ). Moreover, the p53-mediated nucleolar stress response is retained in NPM1 -mutated AML because NPM1 -mutated AML cells lack p53 mutations . . .

Mutations of Nucleophosmin ( NPM1 ) are the most common genetic abnormalities in adult acute myeloid leukaemia (AML), accounting for about 30% of cases. NPM1 -mutated AML has been recognized as distinct entity in the 2017 World Health Organization (WHO) classification of lympho-haematopoietic neoplasms. WHO criteria allow recognition of this leukaemia entity and its distinction from AML with myelodysplasia-related changes, AML with BCR-ABL1 rearrangement and AML with RUNX1 mutations. Nevertheless, controversial issues include the percentage of blasts required for the diagnosis of NPM1 -mutated AML and whether cases of NPM1 -mutated myelodysplasia and chronic myelomonocytic leukaemia do exist. Evaluation of NPM1 and FLT3 status represents a major pillar of the European LeukemiaNet (ELN) genetic-based risk stratification model. Moreover, NPM1 mutations are particularly suitable for assessing measurable residual disease (MRD) since they are frequent, stable at relapse and do not drive clonal haematopoiesis. Ideally, combining monitoring of MRD with the ELN prognostication model can help to guide therapeutic decisions. Here, we provide examples of instructive cases of NPM1 -mutated AML, in order to provide criteria for the appropriate diagnosis and therapy of this frequent leukaemia entity.

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

The Epstein–Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a “hit-and-run” mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.

A patient with clonal hematopoiesis of indeterminate potential (CHIP) received the diagnosis of lymphoma with activation of RHOA . Approximately 1 year later, NPM1 -mutated acute leukemia developed with the same CHIP mutations but without mutated RHOA .

Background RNA-Seq is an increasing used methodology to study either coding and non-coding RNA expression. There are many software tools available for each phase of the RNA-Seq analysis and each of them uses different algorithms. Furthermore, the analysis consists of several steps regarding alignment ( primary-analysis ), quantification, differential analysis ( secondary-analysis ) and any tertiary-analysis and can therefore be time-consuming to deal with each step separately, in addition to requiring a computer knowledge. For this reason, the development of an automated pipeline that allows the entire analysis to be managed through a single initial command and that is easy to use even for those without computer skills can be useful. Faced with the vast availability of RNA-Seq analysis tools, it is first of all necessary to select a limited number of pipelines to include. For this purpose, we compared eight pipelines obtained by combining the most used tools and for each one we evaluated peak of RAM, time, sensitivity and specificity. Results The pipeline with shorter times, lower consumption of RAM and higher sensitivity is the one consisting in HISAT2 for alignment, featureCounts for quantification and edgeR for differential analysis. Here, we developed ARPIR, an automated pipeline that recurs by default to the cited pipeline, but it also allows to choose, between different tools, those of the pipelines having the best performances. Conclusions ARPIR allows the analysis of RNA-Seq data from groups undergoing different treatment allowing multiple comparisons in a single launch and can be used either for paired-end or single-end analysis. All the required prerequisites can be installed via a configuration script and the analysis can be launched via a graphical interface or by a template script. In addition, ARPIR makes a final tertiary-analysis that includes a Gene Ontology and Pathway analysis . The results can be viewed in an interactive Shiny App and exported in a report ( pdf , word or html formats). ARPIR is an efficient and easy-to-use tool for RNA-Seq analysis from quality control to Pathway analysis that allows you to choose between different pipelines.

RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2′-O-methylation (2′-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2′-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2′-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure. We identify NPM1 germline mutations in patients with dyskeratosis congenita presenting with bone marrow failure and demonstrate that they are deficient in small nucleolar RNA binding. Mice harboring a dyskeratosis congenita germline Npm1 mutation recapitulate both hematological and nonhematological features of dyskeratosis congenita. Thus, our findings indicate that impaired 2′-O-Me can be etiological to human disease. NPM1 regulates ribosomal RNA 2′-O-methylation by binding to small nucleolar RNAs, thereby modulating translation. NPM1 mutations lead to altered 2′-O-methylation and impaired ribosomal function, resulting in bone marrow failure and leukemia susceptibility.