medRxiv - Hematology最新文献

{"title":"Machine Learning Insights into HLA Noncoding Sequence Mismatches and Their Impact on DPB1 Matching in Hematopoietic Cell Transplantation","authors":"Medhat Askar, Timothy L. Mosbruger, Grace Tzun-Wen Shaw, Haedong Kim, Yuncheng Duan, Andrew S. Allen, Jamie L. Duke, Timothy S. Olson, Dimitri S. Monos, Tristan J. Hayeck","doi":"10.1101/2024.09.13.24313580","DOIUrl":"https://doi.org/10.1101/2024.09.13.24313580","url":null,"abstract":"Purpose: HCT is vital for treating hematological malignancies, relying on HLA matching between unrelated patient-donor pairs to significantly reduce adverse outcomes. Recent studies recognize the potential impact of HLA-DPB1 mismatches on HCT outcomes. Multiple approaches focus on finding better-tolerated HLA-DPB1 mismatches. Additionally, recent studies suggest matching at noncoding HLA sequence may improve HCT outcomes. This study aims to evaluate different approaches for categorizing DPB1 mismatches in patient-donor pairs and explore the potential impact of noncoding mismatches (available in class I HLA genes) on clinical outcomes. Methods: A retrospective study of 5,106 HCT pairs using Cox proportional hazards models, weighted by a machine learning algorithm, evaluates the impact of particular combinations of HLA-DPB1 mismatches in the context of noncoding HLA class I mismatches on outcomes of HCT. HLA-DPB1 mismatch criteria included T-cell epitope permissive/non-permissive mismatches, expression markers, and evolutionary clade mismatches. Results: Two HLA-DPB1 mismatches, using multiple criteria, lead to significant hazards of acute graft versus host disease grades 2-4, in the T cell replete group. When HLA-DPB1 mismatches occurred across evolutionary clades (DP2 allele/low-expression patient vs DP5 allele/high-expression in the donor), the deplete group showed significant hazards for treatment-related mortality (TRM) (HR=1.94, p-value=8.9x10-7) and overall survival (OS) (HR=1.67, p-value=1.3 x10-5) for additive effects of noncoding mismatches with two HLA-DPB1 mismatches. Conclusion: Two HLA-DPB1 mismatches remain to predict worse outcomes. However, noncoding mismatches in HLA class I genes confer elevated hazards of TRM and OS in conjunction with mismatches across evolutionary branches of HLA-DPB1. Therefore, noncoding mismatches may inform donor selection in the presence of HLA-DPB1 mismatches and improve HCT outcomes, emphasizing the utility of comprehensive sequencing of HLA alleles in HCT settings.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of haemoglobin concentration measurements using HemoCue-301 and Sysmex XN-Series 1500: a survey among anaemic Gambian infants aged 6-12 months","authors":"Mamadou Bah, Hans Verhoef, Abdou Camara, Morris Nden Ngom, Demba Jallow, Kebba Bajo, Foday Bah, Maarten Pleij, Maaike Klappe, Alasana Saidykhan, Emmanuel Okoh, Abdoulie Bah, Carla Cerami","doi":"10.1101/2024.09.05.24313093","DOIUrl":"https://doi.org/10.1101/2024.09.05.24313093","url":null,"abstract":"<strong>Background &amp; Aims</strong> In low-income countries, point-of-care photometers are used in the screening and management of anaemia in individuals, but also in the assessment of population iron status when evaluating efficacy of intervention studies or public health interventions. We aimed to evaluate the accuracy of a commonly used photometer, HemoCue-301, in determining haemoglobin concentration among anaemic children aged 6-12 months in a field setting in rural Africa.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of Common Deletion Mutations (− α3.7 and − α4.2 kb) in HBA gene and Genotype-Phenotype Correlation","authors":"Satarupta Basu, Soma Gupta, Rajib De, Shuvra Neel Baul, Aditi Sen, Shreyashi Dasgupta, Arindam Biswas","doi":"10.1101/2024.09.03.24312976","DOIUrl":"https://doi.org/10.1101/2024.09.03.24312976","url":null,"abstract":"<strong>Background and Objectives</strong> Microcytic hypochromic anemia is the most common feature of alpha-thalassemia and depends on the number of alpha genes deleted. Therefore, in this study, we aim to determine the most common deletion mutations among microcytic anemia cases of West Bengal and correlate them with different biochemical parameters and endophenotypes.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic and functional screening reveal targetable vulnerabilities in TP53 mutated multiple myeloma","authors":"Dimitrios Tsallos, Nemo K. Ikonen, Juho J. Miettinen, Muntasir M. Majumder, Samuli Eldfors, Imre Västrik, Alun Parsons, Minna Suvela, Katie Dunphy, Paul Dowling, Despina Bazou, Peter O'Gorman, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Caroline A. Heckman","doi":"10.1101/2024.08.23.24312359","DOIUrl":"https://doi.org/10.1101/2024.08.23.24312359","url":null,"abstract":"Despite development of several effective therapies for multiple myeloma (MM), the prognosis of patients with partial deletion of chromosome 17 (del(17p)) and <em>TP53</em> aberrations remains poor. By applying comprehensive multi-omics profiling analyses (whole exome and transcriptome sequencing plus proteomics) and functional ex vivo drug screening to samples from 167 patients with MM, we uncovered novel therapeutic vulnerabilities specific to <em>TP53</em> mutated MM. Our findings revealed a distinct sensitivity profile to a range of inhibitors (mitotic, topoisomerase, HDAC, HSP90, IGF1R and PI3K/AKT/mTOR inhibitors) irrespective of 17p deletion status. Conversely, no increase in sensitivity was observed for monoallelic <em>TP53</em> (del(17p) with WT <em>TP53</em>) when compared to WT <em>TP53</em> samples, highlighting the remaining unmet clinical need. Notably, plicamycin, an RNA synthesis inhibitor linked to modulation of chromatin structure and increased transcription, emerged as particularly efficacious for <em>TP53</em> mutated MM. The increased sensitivity correlated with higher protein expression of the drug targets: HDAC2, HSP90AA1 and multiple ribosomal subunits. Additionally, we observed increased RNA expression of G2M checkpoint, E2F targets and mTORC1 signaling in our cohort and the MMRF-CoMMpass (NCT01454297) study in <em>TP53</em> mutated MM. Harmonization of multi-omics data with ex vivo drug screening results revealed that <em>TP53</em> mutated MM is functionally distinct from MM with monoallelic <em>TP53</em>, and demonstrate that MM with mutated <em>TP53</em>, with and without del(17p), may be targetable by approved drugs, and further indicates the need for regular monitoring by sequencing to identify these patients.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the Therapeutic Effects of Amino Acid Treatment on Vaso-Occlusive Pain in Sickle Cell Disease: A Systematic Review and Meta-Analysis Protocol","authors":"Bohan Zhang, Ciaran Bubb, Vivian Dong, Sophie Yao, Priyal Patel, Aanya Shahani, Katie Lobner, Oluwakemi Badaki-Makun","doi":"10.1101/2024.08.08.24311691","DOIUrl":"https://doi.org/10.1101/2024.08.08.24311691","url":null,"abstract":"Introduction: Sickle Cell Disease (SCD) affects over 100,000 individuals in the United States and 20 million globally, causing acute and chronic pain. The disease is characterized by misshapen red blood cells caused by mutations in beta-hemoglobin genes. SCD leads to multiorgan damage, chronic anemia, and severe pain crises, with a median life expectancy of 43 years. Current treatments involve opioids, blood transfusions, and hydroxyurea. Amino acids, especially L-Glutamine, have shown promise in managing SCD pain. This systematic review aims to comprehensively analyze the effects of amino acid treatments on vaso-occlusive pain crises in SCD patients.\u0000Methods: Following the Cochrane Handbook and PRISMA-P guidelines, this systematic review will include studies comparing amino acid treatment to placebo or standard care for SCD pain crises. Eligible studies of all age ranges, settings, and amino acid types will be considered. A comprehensive search strategy will be employed in PubMed, Embase, and Scopus databases. Studies will be assessed for risk of bias using Cochrane's RoB2 tool. Primary outcomes include a reduction in pain, measured quantitatively through pain scales. Secondary outcomes encompass quality of life, hospital length of stay, and opioid equivalents used.\u0000Discussion: Existing literature underscores the therapeutic potential of amino acids, yet there still lacks a systematic review comparing the overall effects of different amino acid treatments for vaso-occlusive crises in patients with SCD. This review aims to serve as a valuable resource for clinicians, offering insights into amino acid interventions as alternatives or supplements to opioid treatments. Additionally, it seeks to encourage further randomized clinical trials, contributing to an informed clinical use of amino acids for pain management in SCD. Ultimately, the findings aim to enhance the understanding of the therapeutic effects of essential amino acids on pediatric patients with SCD, facilitating evidence-based clinical decisions.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"2011 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Response to Azacitidine in Myelodysplastic Neoplasms is Associated with Distinct DNA Methylation Changes in Haematopoietic Stem and Progenitor cells in vivo","authors":"Julie A.I. Thoms, Feng Yan, Henry R. Hampton, Sarah Davidson, Swapna Joshi, Jesslyn Saw, Chowdhury H. Sarowar, Xin Ying Lim, Andrea C. Nunez, Purvi M. Kakadia, Golam Sarower Bhuyan, Xiaoheng Zou, Mary Nguyen, Elaheh S. Ghodousi, Forrest C. Koch, Fatemeh Vafaee, Russell Pickford, Mark J. Raftery, Sally Hough, Griselda Buckland, Michelle Bailey, Yuvaraj Ghodke, Noorul Absar, Lachlin Vaughan, Leonardo Pasalic, Chun Y. Fong, Melita Kenealy, Devendra K. Hiwase, Rohanna I. Stoddart, Soma Mohammed, Linda Lee, Freda H. Passam, Stephen R. Larsen, Kevin J. Spring, Kristen K. Skarratt, Patricia Rebeiro, Peter Presgrave, William S. Stevenson, Silvia Ling, Campbell Tiley, Stephen J. Fuller, Fernando Roncolato, Anoop K. Enjeti, Dirk Hoenemann, Charlotte Lemech, Christopher J. Jolly, Stefan K. Bohlander, David J. Curtis, Jason W.H. Wong, Ashwin Unnikrishnan, Mark Hertzberg, Jake Olivier, Mark N. Polizzotto, John E. Pimanda","doi":"10.1101/2024.07.19.24310679","DOIUrl":"https://doi.org/10.1101/2024.07.19.24310679","url":null,"abstract":"Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"38 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141769372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infectious Complications Following CD30 Chimeric Antigen Receptor T-Cell Therapy in Adults","authors":"Felicia Cao, Yueling Xiu, Michael Mohnasky, Jonathan S Serody, Paul Armistead, Gianpietro Dotti, Melody Smith, Jonathan Huggins, Julia Messina, Bhanu Ramachandran, Jennifer Saullo, Joseph Stromberg, Manish K Saha, Megan Walsh, Barbara Savoldo, Natalie Grover, Heather I Henderson, Tessa M. Andermann","doi":"10.1101/2024.07.10.24310235","DOIUrl":"https://doi.org/10.1101/2024.07.10.24310235","url":null,"abstract":"Infections are increasingly recognized as a common complication of chimeric antigen receptor (CAR) T-cell therapy. The incidence of clinically-defined infection after CD19.CAR T-cell therapy for relapsed/refractory lymphoma ranges from 60-90% in the first year after CAR T-cell therapy and is the most common cause for non-relapse mortality. However, infectious risk after CAR T-cell therapy targeting other malignancies is not well understood. Herein, we report for the first time, infectious complications after CD30.CAR T-cell treatment for patients with Hodgkin's lymphoma and peripheral T-cell lymphoma. Since CD30 is only expressed on a subset of activated T and B-cells, we hypothesized that CD30.CAR T-cell patients would have reduced incidence and severity of infections after infusion compared to CD19.CAR T-cell patients. We retrospectively evaluated all 64 patients who received CD30.CAR T-cells at a single institution between 2016-2021, and assessed infections within one year after cell infusion, comparing these data to a contemporary cohort of 50 patients who received CD19.CAR T-cells at the same institution between 2018-2021. 23 CD30.CAR T-cell patients (36%) and 18 CD19.CAR T-cell patients (36%) developed a microbiologically confirmed infection. Infection severity and bacterial infections were higher in the CD19.CAR T-cell group compared to CD30.CAR T-cell recipients who more commonly had grade 1 respiratory viral infections. Our data reflect expected outcomes for severity and infection type in CD19.CAR T-cell patients and provide a benchmark for comparison with the novel CD30.CAR T-cell product. Although our findings require replication in a larger cohort, they have implications for antimicrobial prophylaxis guidelines after CD30.CAR T-cell therapy.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An integrated multi-omics investigation of W-NK1, a cytokine-primed non-engineered natural killer cell therapy product","authors":"Laura Arthur, Nitin Mahajan, Jayakumar Vadakekolathu, Tom Leedom, David J Boocock, Clare Coveney, Alex Hamil, Kristann Magee, John Dean, Elizabeth Schramm, Benjamin Capoccia, Vincent Petit, Nupur Bhatnagar, Christian Pinset, Aways Younis, Craig Doig, Benjamin Thomas, Evangelia Williams, Lena Luukkonen, Yanira Ruiz-Heredia, Alejandro Martin Munoz, Paola Comune Pennacchi, Daniel Primo, Neysa Dagostino, Stacy K Lewis, Natasha Edwin, John Muth, Melissa Berrien-Elliott, Todd A Fehniger, Jan K Davidson-Moncada, Sergio Rutella","doi":"10.1101/2024.07.08.24310018","DOIUrl":"https://doi.org/10.1101/2024.07.08.24310018","url":null,"abstract":"Background Natural killer (NK) cells originate from bone marrow precursors and mediate effective anti-tumor responses. Clinical trials of cytokine-primed memory-like (ML) NK cells in acute myeloid leukemia (AML) have demonstrated activity without major toxicity, including graft-versus-host disease or cytokine release syndrome. However, broad application of non-expanded, non-engineered ML NK cells has been hindered by limited availability of NK cells from a single donor, thereby precluding aggressive dose escalation and repeat dosing. W-NK1 is derived from human peripheral blood mononuclear cells undergoing ML reprogramming with a proprietary heteromeric fusion protein complex including IL-12, IL-15 and IL-18.\u0000Methods We conducted a multi-omics characterization of W-NK1 by interrogating its transcriptomic, proteomic and metabolic profile. Using functional assays, we assessed W-NK1s cytotoxicity under adverse culture conditions, as well as W-NK1s trafficking and killing abilities in immunodeficient mice engrafted with THP-1 AML. Finally, we evaluated W-NK1s phenotype and in vivo expansion kinetics in one patient with AML enrolled in study NCT05470140.\u0000Results W-NK1 displayed an activated, hyper-metabolic, and proliferative state differing from unstimulated conventional NK cells (cNK) from healthy donors. When compared to external single-cell NK datasets, W-NK1 was largely annotated as NKG2A+ and showed low relatedness with adaptive NK states characterized by HCMV-induced inflammatory memory. W-NK1 outperformed cNK cells in terms of in vitro killing of a broad panel of AML cell lines, with no appreciable cytotoxicity against normal cell lines. The expression of nutrient transporters was higher in W-NK1 compared to cNK cells and was retained even in adverse culture conditions designed to mimic an immunosuppressive tumor microenvironment. In mice engrafted with THP-1 AML, W-NK1 trafficked and efficiently homed to the bone marrow, where it mediated better tumor control than cNK cells. W-NK1 expanded, underwent phenotypic changes and persisted with effective elimination of circulating AML blasts through day 14 after infusion in one patient treated on clinical trial NCT05470140. Immunofluorescence staining of BM sections collected on day 28 showed increased expression of both CD56 and CD3 compared to a pre-treatment biopsy.\u0000Conclusions Our study offers a comprehensive characterization of W-NK1 as an effective cell therapy product for AML and solid tumor malignancies.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141572146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Anemia of Chronic Disease/Inflammation at a Tertiary Care Hospital in North India","authors":"Sidheshwar Vishnu Bhendekar, Jay Kirtani, Rahul Naithani","doi":"10.1101/2024.06.26.24309451","DOIUrl":"https://doi.org/10.1101/2024.06.26.24309451","url":null,"abstract":"Background: There is lack of data from India on prevalence of anemia of chronic disease or inflammation (ACD). Patients &amp; methods: This was a prospective observational cross sectional prevalence study. Anemic patients underwent a complete blood count with peripheral smear, serum ferritin level, iron, total iron binding capacity, transferrin saturation, vitamin B12 and folic acid level, reticulocyte count and stool for occult blood. Other investigations were performed as required according to patients clinical profile. Results: Three hundred fifty five patients were enrolled. A total of 109 patients (30.7%) had anemia of chronic disease ACD (30.7%). Sixty three/263 (24%) females had ACD compared to 46/95 (48.4%) males. ACD was four times more common in age group 80 years and above (56.5%) compared to age group 18 to 39 years (13.9%). Seventy two (66%) patients had mild anemia, 19 patients (17%) had moderate anemia and 18 patients (16%) had severe anemia. Diabetes mellitus (44%), hypertension (39%) and chronic kidney disease (25%) were the commonest underlying morbidity. Thirty six patients (33%) had no underlying comorbidity or cause. Conclusion: The prevalence of anemia of chronic disease increases with age. Majority of anemia of chronic disease patients have mild anemia.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution","authors":"Kane A Foster, Elise Rees, Louise Ainley, Eileen M Boyle, Lydia Lee, Gwennan Ward, Daria Galas-Filipowicz, Anna Mikolajczak, Emma J Lyon, Dylan Jankovic, Jasmine Rahman, Mahima Turakhia, Imran Uddin, Gordon Beattie, Yvette Hoade, Catherine Zhu, James L Reading, Ieuan G Walker, Michael A Chapman, Karthik Ramasamy, Javier Herrero, Benny Chain, Sergio A Quezada, Kwee Yong","doi":"10.1101/2024.06.22.24309250","DOIUrl":"https://doi.org/10.1101/2024.06.22.24309250","url":null,"abstract":"The haematological malignancy multiple myeloma is associated with skewed T-cell activation and function. T-cell alterations are detectable in asymptomatic myeloma precursor conditions and have the potential to identify precursor patients at imminent risk of progression. However, what myeloma-associated T-cells alterations represent mechanistically, how they relate to tumour burden and gene expression, and what influences high inter-patient variability in immune composition remains unknown. Here, we assembled the largest ever dataset of published and newly-generated single-cell RNA and TCR sequencing of the marrow and blood from patients with myeloma, precursor conditions, and age-matched non-cancer controls. We show myeloma is not associated with T-cell exhaustion and instead defined by a pattern of T-cell differentiation resembling antigen-driven terminal memory differentiation. Myeloma-associated T-cell differentiation was dependent on tumour-intrinsic features including tumour burden and tumour expression of antigen-presentation genes. Expanded TCR clones accumulating in myeloma were not enriched for viral specificity and were detected in effector states in highly infiltrated marrows. Together, these results suggest anti-tumour immunity drives a novel form of cancer-associated T-cell memory differentiation in myeloma.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}