Blood Neoplasia最新文献

{"title":"Correlation between peripheral blood and bone marrow mutations among patients with MDS from the National MDS Study","authors":"","doi":"10.1016/j.bneo.2024.100026","DOIUrl":"10.1016/j.bneo.2024.100026","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100026"},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000268/pdfft?md5=97df9812d425700a9a623ad4d99c9d22&pid=1-s2.0-S2950328024000268-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141396921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An EMT-like signature as a potential driver of myeloid sarcoma","authors":"","doi":"10.1016/j.bneo.2024.100024","DOIUrl":"10.1016/j.bneo.2024.100024","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100024"},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000244/pdfft?md5=f4c347d89c3cc3c7ab678a4d0d1c7f40&pid=1-s2.0-S2950328024000244-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141401036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ibrutinib dose adjustment on TTNT in first-line CLL/SLL: a real-world analysis using target trial emulation","authors":"","doi":"10.1016/j.bneo.2024.100022","DOIUrl":"10.1016/j.bneo.2024.100022","url":null,"abstract":"<div><h3>Abstract</h3><p>Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, is a standard-of-care first-line (1L) treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Dosing flexibility (adjustment to daily dose of &lt;420 mg/d) with ibrutinib can help prevent recurrence or worsening of adverse events while maintaining long-term efficacy. This study compared time to next treatment among patients with CLL/SLL in the United States initiating 1L single-agent ibrutinib at 420 mg/d (index date) and staying on this dose vs patients with dose adjustment (DA) within 3 to 12 months. Two databases were used: Komodo claims (a majority from community practices) and Acentrus electronic medical records (from academic and nonteaching hospital systems). To account for immortal time bias (patients with DA survived on 1L therapy until DA) and overlap between follow-up time and definition of treatment strategies, a target trial emulation approach was used, in which patients were cloned at index date and contributed follow-up to both treatment strategy arms until deviation from the strategy. Among 3343 patients in Komodo (mean age: 67.5 years; 37.6% female) and 1171 patients in Acentrus (mean age: 70.4 years; 34.6% female) who initiated 1L single-agent ibrutinib 420 mg/d, 18.0% and 19.6%, respectively, had a DA. DA was not associated with an increased risk of having a next treatment in both databases (adjusted hazard ratio [95% confidence interval]: Komodo: 0.95 [0.80-1.14], Acentrus: 1.14 [0.80-1.62]). These findings suggest that a flexible dosing approach with ibrutinib may be effective in allowing patients to achieve optimal outcomes while remaining on long-term continuous 1L treatment.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100022"},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000220/pdfft?md5=51d92c6d6c422926088b47d7e3e1747f&pid=1-s2.0-S2950328024000220-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141408894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional multiomics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma","authors":"Priya Choudhry ,&nbsp;Corynn Kasap ∗ ,&nbsp;Bonell Patiño-Escobar ∗ ,&nbsp;Olivia Gugliemini ,&nbsp;Huimin Geng ,&nbsp;Vishesh Sarin ,&nbsp;Amrik Kang † ,&nbsp;Audrey Kishishita † ,&nbsp;Sham Rampersaud † ,&nbsp;Letitia Sarah ,&nbsp;Yu-Hsiu T. Lin ,&nbsp;Neha Paranjape ,&nbsp;Poornima Ramkumar ,&nbsp;Jonathan C. Patton ,&nbsp;Makeba Marcoulis ,&nbsp;Donghui Wang ,&nbsp;Paul Phojanakong ,&nbsp;Veronica Steri ,&nbsp;Byron Hann ,&nbsp;Benjamin G. Barwick ,&nbsp;Arun P. Wiita","doi":"10.1016/j.bneo.2024.100025","DOIUrl":"10.1016/j.bneo.2024.100025","url":null,"abstract":"<div><h3>Abstract</h3><p>CD38 is a surface ectoenzyme expressed at high levels on myeloma plasma cells and is the target for the monoclonal antibodies (mAbs) daratumumab and isatuximab. Pretreatment CD38 density on tumor cells is an important determinant of mAb efficacy. Several small molecules have been found to increase tumor surface CD38, with the goal of boosting mAb efficacy in a cotreatment strategy. Numerous other CD38-targeting therapeutics are currently in preclinical or clinical development. Here, we sought to extend our currently limited insight into CD38 surface expression by using a multiomics approach. Genome-wide CRISPR interference screens integrated with patient–centered epigenetic analysis confirmed known regulators of <em>CD38</em>, such as RARA, while revealing XBP1 and SPI1 as other key transcription factors governing surface CD38 levels. <em>CD38</em> knockdown followed by cell surface proteomics demonstrated no significant remodeling of the myeloma “surfaceome” after genetically induced loss of this antigen. Integrated transcriptome and surface proteome data confirmed high specificity of all-trans retinoic acid in upregulating CD38, in contrast to the broader effects of azacytidine and panobinostat. Finally, unbiased phosphoproteomics identified inhibition of MAP kinase pathway signaling in tumor cells after daratumumab treatment. Our work provides a resource to design strategies to enhance efficacy of CD38-targeting immunotherapies in myeloma.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100025"},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000256/pdfft?md5=a27e6b08696b724b63d2d012e38a44b2&pid=1-s2.0-S2950328024000256-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium","authors":"","doi":"10.1016/j.bneo.2024.100023","DOIUrl":"10.1016/j.bneo.2024.100023","url":null,"abstract":"<div><h3>Abstract</h3><p>Histiocytic disorders are rare hematologic neoplasms characterized by a notable dependence on mitogen-activated protein kinase signaling. Targeted therapy is an emerging treatment option, yet the number of reported patients remains limited. Here, we describe 40 patients with histiocytic neoplasms who were treated with targeted therapy in 7 tertiary referral hospitals from the Netherlands and Belgium. The cohort comprised of 6 (15%) children and 34 (85%) adults with diverse histiocytoses, including Langerhans cell histiocytosis (LCH; n = 12), Erdheim–Chester disease (n = 14), central nervous system xanthogranuloma (n = 2), Rosai–Dorfman disease (n = 3), histiocytic sarcoma (n = 2), ALK–positive histiocytosis (n = 1), and mixed/unclassifiable histiocytosis (n = 6). Five patients were included in a clinical trial; 35 (88%) received BRAF/MEK inhibitors outside of trials. Among these 35 patients with available follow-up data, median time on targeted treatment was 1.9 years (range, 0.04-5.8 years). Complete or partial responses were observed in 25 of 27 (93%) patients treated for multisystemic and/or solid lesions and 2 of 8 (25%) patients treated for neurodegenerative LCH. Responses were generally durable, although 10 patients lost response after dose reduction or therapy interruption. Responses were recaptured in 9 of 10 cases. Two patients developed new or progressive neurodegenerative lesions: 1 during and 1 after vemurafenib therapy. At last follow-up, 8 adults had stopped targeted therapy because of toxicity. This study corroborates the favorable outcomes of BRAF/MEK inhibition in patients with histiocytosis described previously. However, it also highlights limitations and calls for prospective studies.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100023"},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000232/pdfft?md5=d4a89468e3562c13ebf6916d17549241&pid=1-s2.0-S2950328024000232-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141403218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venetoclax and hypomethylating agents in octogenarians and nonagenarians with acute myeloid leukemia","authors":"Ellen Madarang ,&nbsp;Jillian Lykon ,&nbsp;Wei Zhao ,&nbsp;Mikkael A. Sekeres ,&nbsp;Terrence Bradley ,&nbsp;Namrata S. Chandhok ,&nbsp;Justin Taylor ,&nbsp;Sangeetha Venugopal ,&nbsp;Tulay Koru-Sengul ,&nbsp;Sunil Girish Iyer ,&nbsp;Jason S. Gilbert ,&nbsp;Ryan M. Miller ,&nbsp;Jacopo Nanni ,&nbsp;Irene Zacheo ,&nbsp;Agnese Mattei ,&nbsp;Najla Al Ali ,&nbsp;Ashwin Kishtagari ,&nbsp;Giovanni Marconi ,&nbsp;David A. Sallman ,&nbsp;Daniel A. Pollyea ,&nbsp;Justin Watts","doi":"10.1016/j.bneo.2024.100016","DOIUrl":"10.1016/j.bneo.2024.100016","url":null,"abstract":"<div><h3>Abstract</h3><p>Venetoclax (VEN) plus a hypomethylating agent (HMA) regimen is the standard of care for older adults with acute myeloid leukemia (AML); however, it is associated with significant myelosuppression and complications, potentially limiting its use in those who are very old. We performed a multicenter retrospective analysis of VEN-HMA treatment in octogenarians and nonagenarians to further understand the tolerability, feasibility, dosing considerations, and clinical efficacy in this unique group. Patients with AML aged ≥80 years who received VEN-HMA between March 2015 and April 2022 were reviewed. VEN-HMA dosing was determined by treating physician, accounting for CYP3A4 drug interaction dose adjustments. In total, 154 patients were included, with a median age of 82 years (range, 80-92), who received treatment with VEN-HMA (83% with azacitidine and 17% with decitabine). Most patients (53%) had European LeukemiaNet 2017 adverse risk AML, 33% had intermediate, 8% had favorable, and 6% were unknown. With a median follow-up of 7.7 months, 36 patients (23%) remained in remission, with 31 (20%) still on VEN-HMA. The 30-day and 60-day mortality rates were 8.5% and 17%, respectively. The composite complete remission (CRc) rate for patients with newly diagnosed AML without prior myelodysplastic syndrome was 73% (48 of 66). Median overall survival (OS) was 8.1 months, and in patients who achieved a response (CRc), median OS was 13.2 months. Landmark analysis from the time CRc was first achieved showed that patients receiving VEN for ≤14 days had improved OS; median, 24.0 months. Patients who are very old can be treated safely with combination VEN-HMA with expectations of dose reductions and cycle extensions to ensure tolerability over the long term.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 2","pages":"Article 100016"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000165/pdfft?md5=d6c6fab40ecf4f727e977362cb0cfbff&pid=1-s2.0-S2950328024000165-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141058132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The landscape of rare genetic variants in familial Waldenström macroglobulinemia","authors":"Alexander Pemov ,&nbsp;Jung Kim ,&nbsp;Wen Luo ,&nbsp;Jia Liu ,&nbsp;Cole Graham ,&nbsp;Kristine Jones ,&nbsp;Delphine DeMangel ,&nbsp;Neal D. Freedman ,&nbsp;Charles Dumontet ,&nbsp;Bin Zhu ,&nbsp;Mary L. McMaster ,&nbsp;Douglas R. Stewart","doi":"10.1016/j.bneo.2024.100013","DOIUrl":"10.1016/j.bneo.2024.100013","url":null,"abstract":"<div><h3>Abstract</h3><p>Waldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in <em>TREX1</em> and <em>SAMHD1</em> (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, <em>POT1, RECQL4, PTPN11, PMS2</em>). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 2","pages":"Article 100013"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S295032802400013X/pdfft?md5=7d264d4490d9a6245a10e30efcc10a9c&pid=1-s2.0-S295032802400013X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140784350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD302 predicts achievement of deep molecular response in patients with chronic myeloid leukemia treated with imatinib","authors":"Chung Hoow Kok ,&nbsp;Yazad Irani ,&nbsp;Jade Clarson ,&nbsp;Verity Saunders ,&nbsp;Phuong Dang ,&nbsp;Naranie Shanmuganathan ,&nbsp;Susan Branford ,&nbsp;David Yeung ,&nbsp;Agnes S. M. Yong ,&nbsp;Timothy P. Hughes","doi":"10.1016/j.bneo.2024.100014","DOIUrl":"https://doi.org/10.1016/j.bneo.2024.100014","url":null,"abstract":"<div><h3>Abstract</h3><p>Achieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month <em>BCR</em>::<em>ABL1</em>% (PR-1), or high <em>CD302</em> expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; <em>P</em> &lt; .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; <em>P</em> = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle–related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34⁺CD302⁺ and CD14⁺CD302⁺ cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 2","pages":"Article 100014"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000141/pdfft?md5=203d3abae466c2edbbfccec17f07d8a0&pid=1-s2.0-S2950328024000141-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141240049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS","authors":"Jad Othman ,&nbsp;Ho Pui Jeff Lam ,&nbsp;Sarah Leong ,&nbsp;Faisal Basheer ,&nbsp;Islam Abdallah ,&nbsp;Kathryn Fleming ,&nbsp;Priyanka Mehta ,&nbsp;Heba Yassin ,&nbsp;John Laurie ,&nbsp;Michael Austin ,&nbsp;Paolo Gallipoli ,&nbsp;Tom Taylor ,&nbsp;Mike Dennis ,&nbsp;Johnathon Elliot ,&nbsp;Georgina Clarke ,&nbsp;Raymond Dang ,&nbsp;Jennifer Vidler ,&nbsp;Pramila Krishnamurthy ,&nbsp;Anne-Louise Latif ,&nbsp;Pallavi Kalkur ,&nbsp;Richard Dillon","doi":"10.1016/j.bneo.2024.100017","DOIUrl":"10.1016/j.bneo.2024.100017","url":null,"abstract":"<div><h3>Abstract</h3><p>Venetoclax with azacitidine is the standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; however, uncertainties remain regarding the treatment schedule, accurate prognostication, and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available; however, it is not clear for which patients it may be a useful alternative. Here, we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n = 587) or LDAC (n = 67). The median age was 73 years, and 59% had de novo AML. Most patients received 100 mg of venetoclax with an azole antifungal. In cycle 1, patients spent a median of 14 days in the hospital, and 85% required red cell transfusion, 59% platelet transfusion, and 63% required IV antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a complete remission (CR)/CR with incomplete hematological recovery rate of 67%, day 30 and day 60 mortality of 5% and 8%, respectively, and median overall survival of 13.6 months. Mutations in <em>NPM1</em>, <em>RUNX1</em>, <em>STAG2</em>, and <em>IDH2</em> were associated with improved survival, whereas age, secondary and therapy-related AML, +8, <em>MECOM</em> rearrangements, complex karyotype, <em>ASXL1</em>, and <em>KIT</em> mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the European LeukemiaNet and Medical Research Council classifications; however, improved risk classifications are still required. In the 149 patients with <em>NPM1</em> mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100017"},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000177/pdfft?md5=1de290f83adace13a5f6e05842b39ad6&pid=1-s2.0-S2950328024000177-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141136394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Instructive interaction between myelodysplastic hematopoiesis and the bone marrow microenvironment at the single-cell level","authors":"Johann-Christoph Jann ∗ ,&nbsp;Nanni Schmitt ∗ ,&nbsp;Alexander Streuer ,&nbsp;Qingyu Xu ,&nbsp;Vladimir Riabov ,&nbsp;Eva Altrock ,&nbsp;Nadine Weimer ,&nbsp;Verena Nowak ,&nbsp;Julia Obländer ,&nbsp;Iris Palme ,&nbsp;Melda Göl ,&nbsp;Marie Demmerle ,&nbsp;Felicitas Rapp ,&nbsp;Fabian Siegel ,&nbsp;Laurenz Steiner ,&nbsp;Mahmoud Ghazal ,&nbsp;Angelika Duda ,&nbsp;Verena Haselmann ,&nbsp;Ali Darwich ,&nbsp;Ahmed Jawhar ,&nbsp;Daniel Nowak","doi":"10.1016/j.bneo.2024.100021","DOIUrl":"10.1016/j.bneo.2024.100021","url":null,"abstract":"<div><h3>Abstract</h3><p>Myelodysplastic neoplasms (MDS) are hypothesized to remodel their bone marrow (BM) microenvironment to reinforce conditions for their propagation. In this study, we investigated interactions between MDS cells and the BM niche at single-cell level. In a patient-derived xenograft (PDX) model, we analyzed 13 000 cells from different murine niche cell populations after long-term (&gt;24 weeks) exposure to MDS vs healthy human grafts. Subsequently, we analyzed over 24 000 primary human BM cells enriched for the nonhematopoietic compartment by using whole bone fragments from n = 8 patients with MDS and n = 7 healthy, age-matched donors. In PDX who received MDS transplantation, mesenchymal cell (MSC) subpopulations were forced to overexpress hematopoietic factors such as Cxcl12 and Il7 upon contact with hematopoietic MDS cells as compared with healthy grafts. Single-cell analyses of primary in situ BM cells from patients with MDS showed highly heterogeneous MSC subpopulations on a patient-individual level. We identified inflammatory gene expression profiles as well as overexpression of C-X-C Motif Chemokine Ligand 12, KIT ligand, and Interleukin 7 in MDS MSCs and endothelial cells. In conclusion, we demonstrate reprogramming of the BM microenvironment by MDS cells, pointing to altered MSC subpopulations with increased growth factor expression profiles in a subgroup of patients with MDS.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"1 3","pages":"Article 100021"},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000219/pdfft?md5=7e40a71e101380a24de189eb79bb44c9&pid=1-s2.0-S2950328024000219-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}