HemaSphere最新文献

{"title":"Battle of the sexes: Understanding donor:recipient sex differences in transplantation biology","authors":"David G. Kent","doi":"10.1002/hem3.70000","DOIUrl":"https://doi.org/10.1002/hem3.70000","url":null,"abstract":"<p>Studying hematopoietic stem cell (HSC) function is most powerfully done with serial transplantation assays that can formally demonstrate the hallmark functional properties of durability, self-renewal, and multilineage differentiation capacity. Transplantation assays have taken many forms over the decades to provide evidence of HSC function, with mouse:mouse studies representing the bulk of studies to date. Competing for the limelight as a “gold standard” assay for nearly as long, however, is the human HSC:mouse recipient xenotransplantation assay, which has been powerfully used to help define the relative function of both normal HSCs and HSCs isolated from leukemia patients. The latter presents the most urgent need for establishing robust assays in the hematological community. It represents the opportunity to study the function of HSCs isolated from patients with the diseases that we are trying to cure. While there are a number of studies that have used human:human transplantations in clinical settings to study the dynamics of HSCs,<span><sup>1, 2</sup></span> the ability to characterize leukemic HSCs at a detailed molecular level and to treat them with experimental compounds to potentially modify those clonal dynamics for therapeutic purposes remains extremely limited. This is where the xenotransplantation assay comes to the fore, but defining an agreed set of standards in the field is a complex business, and a recent study in <i>HemaSphere</i> by Mian et al. sheds some light on one of the key factors in transplantation biology—sex differences.<span><sup>3</sup></span></p><p>Sex differences in transplantation have been known about for some time, although the studies do not always agree on the how's and why's of these differences. Single HSC transplantation studies in mouse:mouse donor:recipient pairs showed that male HSCs did not perform well in female recipients, potentially due to a weak antigen coded for by the Y chromosome.<span><sup>4</sup></span> Another study,<span><sup>5</sup></span> in human:mouse xenotransplants, showed that female immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice were far superior as recipients of human cells with increases in both engraftment and proliferation of human HSCs (and this was also evidenced at the single-cell level). In this latter study, two potential reasons were speculated: first, that “female NSG mice might be more immunodeficient than males,” and second that “sex-associated factors, such as steroid hormones, can positively or negatively regulate human HSCs.” It is clear that sex matters, but with the emergence of new immunodeficient models and a general lack of comparative studies between male and female recipients, it is difficult to articulate a set of field recommendations for how to undertake xenotransplantation experiments with precious patient samples.</p><p>The recently published study by Mian et al.<span><sup>3</sup></span> goes some way to addressing this. Using various immunodeficient mou","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human immunodeficiency virus-associated Lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","authors":"Kai Hübel, Mark Bower, Igor Aurer, Mariana Bastos-Oreiro, Caroline Besson, Uta Brunnberg, Chiara Cattaneo, Simon Collins, Kate Cwynarski, Alessia D. Pria, Marcus Hentrich, Christian Hoffmann, Marie J. Kersten, Silvia Montoto, Jose-Tomas Navarro, Eric Oksenhendler, Alessandro Re, Josep-Maria Ribera, Philipp Schommers, Bastian von Tresckow, Christian Buske, Martin Dreyling, Andy Davies, the EHA and ESMO Guidelines Committees","doi":"10.1002/hem3.150","DOIUrl":"https://doi.org/10.1002/hem3.150","url":null,"abstract":"<p>Non-Hodgkin lymphoma (NHL) remains the most common type of cancer and a leading cause of mortality in people who are living with human immunodeficiency virus (HIV).<span><sup>1</sup></span> This is despite a marked decrease in the incidence of HIV-associated NHL (HIV–NHL) following the introduction of combination antiretroviral therapy (ART) in the mid-1990s.<span><sup>2</sup></span> In contrast, the incidence of Hodgkin lymphoma (HL) increased slightly but has remained stable since 2000.<span><sup>1</sup></span> Compared with the age- and gender-matched general population, the incidences of HIV–NHL and HIV-associated HL (HIV–HL) are increased ~10- to 20-fold.<span><sup>3</sup></span></p><p>The most common histological types of HIV-associated lymphomas are diffuse large B-cell lymphoma (DLBCL; 37%), HL (26%) and Burkitt lymphoma (BL; 20%).<span><sup>4</sup></span> Independent risk factors for DLBCL in people living with HIV (PLWH) include a low cluster of differentiation (CD)4 T-cell count and an uncontrolled HIV-1 viral load (VL).<span><sup>5</sup></span> The availability of ART and better management of opportunistic infections allow PLWH to receive the same treatments as people without HIV, including intensive therapies, such as autologous stem-cell transplantation (ASCT), allogeneic stem-cell transplantation (allo-SCT) and chimeric antigen receptor T-cell (CAR-T) therapy. Patients with HIV-associated lymphomas should be enrolled in clinical trials whenever possible.</p><p>The aim of this guideline is to provide practical clinical guidance and recommendations to clinicians who manage HIV-associated lymphomas.</p><p>Diagnostic procedures in patients with HIV-associated lymphoma generally mirror those recommended for lymphoma in the general population and those necessary to assess the severity and complications of HIV and its treatment (see Supporting Information S1: Table S1).</p><p>Lymphoma should be diagnosed via tumour biopsy, preferably excisional, that is evaluated by an expert haematopathologist using immunohistochemistry (IHC) and molecular techniques. In exceptional cases when no tumour mass can be biopsied, diagnosis can be made by cytology and flow cytometry.</p><p>Lymphoma staging should involve a contrast-enhanced computed tomography (CT) scan of the neck, chest, abdomen and pelvis and a bone marrow biopsy. A staging [<sup>18</sup>F]2-fluoro-2-deoxy-<span>d</span>-glucose (FDG)–positron emission tomography (PET)–CT scan is more sensitive, especially for extranodal disease. FDG–PET–CT may, however, have a higher false-positive rate in PLWH due to immune deficiency-related lymphoid hyperplasia and non-suppressed HIV infection.<span><sup>6</sup></span> Interim FDG–PET–CT (iFDG–PET–CT) results should, therefore, be interpreted cautiously if used to escalate treatment and when analysing end-of-treatment response; if there is doubt, FDG-avid lesions should be re-biopsied. Otherwise, response criteria do not differ from those used in imm","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes","authors":"Jurrian K. de Kanter,&nbsp;Alexander S. Steemers,&nbsp;Daniel Montiel Gonzalez,&nbsp;Ravian L. van Ineveld,&nbsp;Catharina Blijleven,&nbsp;Niels Groenen,&nbsp;Laurianne Trabut,&nbsp;Marijn A. Scheijde-Vermeulen,&nbsp;Liset Westera,&nbsp;Auke Beishuizen,&nbsp;Anne C. Rios,&nbsp;Frank C. P. Holstege,&nbsp;Arianne M. Brandsma,&nbsp;Thanasis Margaritis,&nbsp;Ruben van Boxtel,&nbsp;Friederike Meyer-Wentrup","doi":"10.1002/hem3.149","DOIUrl":"10.1002/hem3.149","url":null,"abstract":"<p>Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long-term side effects induced by chemo- and radiotherapy. cHL tumors are characterized by the low fraction (0.1%–10%) of malignant Hodgkin and Reed–Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD-1/PD-L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single-cell RNA sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides <i>TNFRSF8</i> (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as <i>NRXN3</i> and <i>LRP8</i>, which can potentially be used as alternative targets for antibody–drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin-1/CD69 and HLA-II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor-immune cell interactions.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term immune changes in patients with relapsed/refractory chronic lymphocytic leukemia following treatment with venetoclax plus rituximab","authors":"Arnon P. Kater,&nbsp;Barbara F. Eichhorst,&nbsp;Carolyn J. Owen,&nbsp;Ulrich Jaeger,&nbsp;Brenda Chyla,&nbsp;Marcus Lefebure,&nbsp;Rosemary Millen,&nbsp;Yanwen Jiang,&nbsp;Maria Thadani-Mulero,&nbsp;Michelle Boyer,&nbsp;John F. Seymour","doi":"10.1002/hem3.146","DOIUrl":"https://doi.org/10.1002/hem3.146","url":null,"abstract":"<p>Immune dysregulation is a hallmark of chronic lymphocytic leukemia (CLL). Anti-CD20 antibodies (e.g., rituximab [R]) can be combined with venetoclax (Ven) to treat CLL. However, anti-CD20 antibodies can increase hypogammaglobulinemia risk, while the effects of Ven on immune dysregulation are still uncertain. We report long-term immune changes in VenR- and bendamustine-R (BR)-treated patients with relapsed/refractory CLL in the MURANO trial (NCT02005471). Patients were randomized to fixed-duration VenR (2 years Ven; VenR for the first 6 months) or BR (6 months). Immune cell levels were evaluated at the end of combination treatment (EOCT), end of treatment (EOT; VenR arm only), and 12 and 24 months post-EOCT. Overall, 130/194 VenR- and 134/195 BR-treated patients completed treatment without progressive disease. In patients who completed VenR combination therapy, median immunoglobulin (Ig)G and IgM levels decreased from baseline to EOT (<i>p</i> ≤ 0.01 and <i>p</i> ≤ 0.0001, respectively); by 24 months, post-EOT IgG had returned to baseline level and IgM had increased from baseline (<i>p</i> ≤ 0.001). Median IgA levels increased from baseline to 12 (<i>p</i> ≤ 0.0001) and 24 months post-EOT (<i>p</i> ≤ 0.0001). In BR-treated patients, changes in IgG, IgA, and IgM levels across the assessed time points were not significant, and by 24 months, post-EOCT IgG, IgA, and IgM were above baseline levels. Grade ≥3 infection rates on treatment were low. Overall, immune recovery was observed with VenR and BR, with stabilization of Ig levels after treatment. Post-treatment infection rates were generally low, making these very tolerable therapies for CLL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142077919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA binding protein-directed control of leukemic stem cell evolution and function","authors":"Pratik Joshi,&nbsp;Ava Keyvani Chahi,&nbsp;Lina Liu,&nbsp;Steven Moreira,&nbsp;Ana Vujovic,&nbsp;Kristin J. Hope","doi":"10.1002/hem3.116","DOIUrl":"10.1002/hem3.116","url":null,"abstract":"<p>Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post–transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post–transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post–transcriptional control as actionable targets for precision therapy of AML.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers of outcome in patients undergoing CD19 CAR-T therapy for large B cell lymphoma","authors":"Inna Y. Gong,&nbsp;Daisy Tran,&nbsp;Samuel Saibil,&nbsp;Rob C. Laister,&nbsp;John Kuruvilla","doi":"10.1002/hem3.130","DOIUrl":"10.1002/hem3.130","url":null,"abstract":"<p>CD19-directed autologous chimeric antigen receptor T cell (CAR-T) therapy has transformed the management of relapsed/refractory (R/R) large B cell lymphoma (LBCL). Initially approved in the third line and beyond setting, CAR-T is now standard of care (SOC) for second-line treatment in patients with refractory disease or early relapse (progression within 12 months) following primary chemoimmunotherapy. Despite becoming SOC, most patients do not achieve complete response, and long-term cure is only observed in approximately 40% of patients. Accordingly, there is an urgent need to better understand the mechanisms of treatment failure and to identify patients that are unlikely to benefit from SOC CAR-T. The field needs robust biomarkers to predict treatment outcome, as better understanding of prognostic factors and mechanisms of resistance can inform on the design of novel treatment approaches for patients predicted to respond poorly to SOC CAR-T. This review aims to provide a comprehensive overview of clinical, molecular, imaging, and cellular features that have been shown to influence outcomes of CAR-T therapy in patients with R/R LBCL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic relevance of molecular measurable residual disease detection in AML with mutated CEBPA","authors":"Christian M. Vonk,&nbsp;Emma L. Boertjes,&nbsp;Francois G. Kavelaars,&nbsp;Melissa Rijken,&nbsp;Jolinda M. L. Konijnenburg,&nbsp;Roxanne E. Cromwell,&nbsp;Bob Löwenberg,&nbsp;Tim Grob,&nbsp;Peter J. M. Valk","doi":"10.1002/hem3.141","DOIUrl":"10.1002/hem3.141","url":null,"abstract":"&lt;p&gt;Mutations in the CCAAT/enhancer binding protein alpha (&lt;i&gt;CEBPA&lt;/i&gt;) are found in 2%–15% (mean 5%) of &lt;i&gt;de novo&lt;/i&gt; acute myeloid leukemia (AML) patients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;CEBPA&lt;/i&gt; encodes a transcription factor that is important for hematopoietic stem cell (HSC) self-renewal as well as myeloid differentiation of hematopoietic progenitors.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The characteristic mutations in the CEBPA protein involve frame-shift mutations in the N-terminal transactivation domains and in-frame mutations in the C-terminal basic leucine zipper (bZIP).&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Recently, the in-frame &lt;i&gt;CEBPA&lt;/i&gt; bZIP mutations were incorporated in the 2022 European LeukemiaNet (ELN) risk classification as a favorable risk factor,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; replacing the &lt;i&gt;CEBPA&lt;/i&gt; double mutations (&lt;i&gt;CEBPA&lt;/i&gt;&lt;sup&gt;dm&lt;/sup&gt;) as favorable marker in the preceding ELN2017 guidelines.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Recent advances in molecular minimal residual disease (MRD) detection in complete remission (CR) have shown profound prognostic value of a selection of AML-specific gene mutations.&lt;span&gt;&lt;sup&gt;5-7&lt;/sup&gt;&lt;/span&gt; However, the prognostic impact of persisting &lt;i&gt;CEBPA&lt;/i&gt; mutations in CR has not been thoroughly investigated in AML patients. Here, we explored the prognostic impact of mutant &lt;i&gt;CEBPA&lt;/i&gt; MRD in a relatively large cohort of 84 AML patients with mutated &lt;i&gt;CEBPA&lt;/i&gt; by deep next-generation sequencing (NGS).&lt;/p&gt;&lt;p&gt;AML patients enrolled in the Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) clinical trials HO42A, HO92, HO102, HO103, and HO132 were included. All trial participants provided written informed consent in accordance with the Declaration of Helsinki, and were treated according to their respective treatment protocol (www.hovon.nl). Patients were assessed for gene mutations on diagnostic bone marrow samples using the TruSight Myeloid Sequencing panel (Illumina) targeting 54 frequently mutated genes in AML.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Since NGS quality and depth of sequencing of the &lt;i&gt;CEBPA&lt;/i&gt; gene varies when using this gene panel, &lt;i&gt;CEBPA&lt;/i&gt; targeted sequencing was additionally performed on DNA of these diagnostic samples using a custom four-amplicon polymerase chain reaction (PCR) approach (amplicons A, B, C1, C2; Supporting Information: Methods).&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; A total of 144 &lt;i&gt;CEBPA&lt;/i&gt; mutant patients out of 1913 AML cases was identified, of which 84 with available CR samples were included for mutant &lt;i&gt;CEBPA&lt;/i&gt; MRD assessment. Targeted deep sequencing was performed on 100 ng of DNA obtained at CR, after two cycles of standard induction chemotherapy and pretransplant, using the four-amplicon PCR-based NGS approach.&lt;span&gt;&lt;sup&gt;8, 9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;At diagnosis, 43 out of 84 cases harbored a mutation in the bZIP region (bzip), whereas 41 carried other mutations (non-bzip) (Supporting Information S1: Table 1). All &lt;i&gt;CEBPA","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robust and cost-effective CRISPR/Cas9 gene editing of primary tumor B cells in Eµ-TCL1 model of chronic lymphocytic leukemia","authors":"Rosita Del Prete,&nbsp;Roberta Drago,&nbsp;Federica Nardi,&nbsp;Gaia Bartolini,&nbsp;Erika Bellini,&nbsp;Antonella De Rosa,&nbsp;Silvia Valensin,&nbsp;Anna Kabanova","doi":"10.1002/hem3.134","DOIUrl":"https://doi.org/10.1002/hem3.134","url":null,"abstract":"&lt;p&gt;Ability to genetically edit primary B cells via CRISPR/Cas9 technology represents a powerful tool to study molecular mechanisms of B-cell pathogenesis. In this context, employing ribonucleoprotein complexes (RNPs), formed by recombinant Cas9 and genome-targetting single guide RNA molecules, brings in advantage of accelerated set-up and protocol robustness. Gene editing via RNP electroporation has been recently applied to primary tumor cells isolated from patients chronic lymphocytic leukemia (CLL), suggesting an efficient and valuable tool for studying leukemic cell biology and biomarker validation.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The work by Nardi et al. on this topic proposed to electroporate unmanipulated primary CLL cells that are subsequently put in culture with human CD40L-expressing fibroblasts and soluble stimuli to promote CLL cell proliferation. In this context, cellular proliferation is required to achieve homozygous gene editing, whereas in unstimulated CLL cells it is possible to achieve only the heterozygous editing.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The method published by Mateos-Jaimez et al. relies on the preactivation of CLL cells with CD40L/BAFF/IL-21-expressing stromal cells, followed by RNP electroporation and continuation of the stimulatory coculture.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Both methods approach 80%–90% of editing efficiency and allow to perform downstream &lt;i&gt;in vitro&lt;/i&gt; experiments on edited leukemic cells.&lt;/p&gt;&lt;p&gt;Application of a similar RNP-based editing approach to the widely used murine model of CLL, the Eμ-TCL1 transgenic mice,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; represents a valuable and versatile tool to explore CLL biology &lt;i&gt;in vivo&lt;/i&gt;. Examples illustrating its feasibility has been first shown in studies by Chakraborthy et al. and Martines et al.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; The published method consists in preactivating primary CD19&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt; leukemic B cells by TLR9 agonist CpG ODN-1668, followed by RNP electroporation and intraperitoneal injection of 30 × 10&lt;sup&gt;6&lt;/sup&gt; electroporated cells to promote expansion of edited leukemic cells &lt;i&gt;in vivo&lt;/i&gt;. Despite this method has been proven effective, it has not been set up to expand edited TCL1 cells &lt;i&gt;in vitro&lt;/i&gt;. This is associated with high experimental costs and does not allow to perform functional analysis of gene editing phenotype prior to the &lt;i&gt;in vivo&lt;/i&gt; transfer, which eventually becomes not feasible if edited cells are unfit &lt;i&gt;in vivo&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;Hence, we envisioned a new approach that would allow to expand RNP-electroporated TCL1 cells &lt;i&gt;in vitro&lt;/i&gt; prior to transfer. To this end, we first optimized culture conditions for TCL1 cells evaluating their viability and proliferation after treatment with different stimuli. We observed that ODN-1668 stimulation, although being efficient in activating TCL1 cells in the short-term,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; does not allow to expand them &lt;i&gt;in vitro&lt;/i&gt; (Supporting Information S1: Figure S1). We thus evaluated","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How to manage patients with germline DDX41 variants: Recommendations from the Nordic working group on germline predisposition for myeloid neoplasms","authors":"Panagiotis Baliakas,&nbsp;Bianca Tesi,&nbsp;Jörg Cammenga,&nbsp;Asbjørg Stray-Pedersen,&nbsp;Kirsi Jahnukainen,&nbsp;Mette Klarskov Andersen,&nbsp;Helena Ågerstam,&nbsp;Maria Creignou,&nbsp;Ingunn Dybedal,&nbsp;Klas Raaschou-Jensen,&nbsp;Kirsten Grønbæk,&nbsp;Outi Kilpivaara,&nbsp;Eva Hellström Lindberg,&nbsp;Ulla Wartiovaara-Kautto","doi":"10.1002/hem3.145","DOIUrl":"10.1002/hem3.145","url":null,"abstract":"<p>Increasing recognition of germline <i>DDX41</i> variants in patients with hematological malignancies prompted us to provide <i>DDX41</i>-specific recommendations for diagnosis, surveillance, and treatment. Causative germline variants in the <i>DDX41</i> predispose to the development of myeloid neoplasms (MNs), especially myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Almost 3%–5% of all patients with MDS or AML carry a pathogenic or likely pathogenic germline <i>DDX41</i> variant, while half of them acquire a somatic second hit in the other allele. <i>DDX41</i>-associated MNs exhibit unique clinical characteristics compared to other hematological malignancies with germline predisposition: MNs occur mostly at advanced age and follow an indolent clinical course. Male carriers are more prone to develop MDS or AML than females. <i>DDX41</i>-associated MN is often hypoplastic, and the malignancy may be preceded by cytopenias.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Don't call me “Sickler”: Confronting stigma in sickle cell disease","authors":"Edeghonghon Olayemi","doi":"10.1002/hem3.137","DOIUrl":"10.1002/hem3.137","url":null,"abstract":"&lt;p&gt;In 2008, the World Health Organization (WHO) declared sickle cell disease (SCD) a public health problem. It is a global disease endemic in sub-Saharan Africa (SSA), where the vast majority of babies with SCD are born annually. Although SCD is considered rare in the European Union (EU), where there has been a gradual increase in prevalence, usually attributed to increased migration from parts of the world such as SSA. Advances in the medical management of SCD have led to a reduction in mortality. This reduction is skewed in favor of patients living in high-income countries, compared to those living in low- and middle-income countries where the disease is endemic. The associated organ damage as a result of increased life expectancy and the higher burden of psycho-social challenges faced daily by millions who live with SCD increases the frequency of interaction between people living with SCD and health care professionals.&lt;/p&gt;&lt;p&gt;The word “sickler” first appeared in the English language over four centuries ago; it was initially used to describe someone who works with a sickle. However, it came to be used to describe a person living with SCD. There is no doubt that it has become a derogatory word. People living with SCD regard being called “a sickler” as negative. They see it as a label that forces them to be seen as different or incapable, making them open to marginalization, stigmatization, and discrimination. It is unfortunate and unacceptable that healthcare workers, including specialist physicians, persist in using the derogatory word. It is still heard in the corridors, wards, and clinics of hospitals across the world. A quick literature search shows that editors and reviewers of medical publications persist in allowing its use, seemingly oblivious to the emotional pain and suffering it brings to the very people health workers are supposed to care for.&lt;/p&gt;&lt;p&gt;Globally, even in countries where it is endemic, SCD is poorly understood. There is a continued high prevalence of stigmatization against people living with SCD. This occurs as a result of society's misunderstanding of SCD. Health stigma has been defined as a social process with the following characteristics: exclusion, rejection, blame, and devaluation resulting from an experience or anticipation of adverse social judgment about a person or group of people who have a specific health problem.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Among people living with SCD, stigma affects every aspect of daily living and may negatively impact relationships with peers, friends, and family.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Stigmatization in SCD care is known to lead to poorer outcomes, such as being reluctant to seek in-hospital care during acute crisis events as patients, over time, develop an aversion to seeking health care services, and when they do, there is often a delay in getting attention and a general poor satisfaction with the care provided. This reluctance has been reported to include obtaining routine health ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 8","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}