Blood最新文献

{"title":"An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA.","authors":"Carlo Castruccio Castracani, Laura Breda, Tyler E Papp, Amaliris Guerra, Enrico Radaelli, Charles-Antoine Assenmacher, Giovanni Finesso, Barbara L Mui, Ying K Tam, Simona Fontana, Chiara Riganti, Veronica Fiorito, Sara Petrillo, Emanuela Tolosano, Hamideh Parhiz, Stefano Rivella","doi":"10.1182/blood.2024025846","DOIUrl":"10.1182/blood.2024025846","url":null,"abstract":"<p><strong>Abstract: </strong>X-linked sideroblastic anemia (XLSA) is a congenital anemia caused by mutations in ALAS2, a gene responsible for heme synthesis. Treatments are limited to pyridoxine supplements and blood transfusions, offering no definitive cure except for allogeneic hematopoietic stem cell transplantation, only accessible to a subset of patients. The absence of a suitable animal model has hindered the development of gene therapy research for this disease. We engineered a conditional Alas2-knockout (KO) mouse model using tamoxifen administration or treatment with lipid nanoparticles carrying Cre-mRNA and conjugated to an anti-CD117 antibody. Alas2-KOBM animals displayed a severe anemic phenotype characterized by ineffective erythropoiesis (IE), leading to low numbers of red blood cells, hemoglobin, and hematocrit. In particular, erythropoiesis in these animals showed expansion of polychromatic erythroid cells, characterized by reduced oxidative phosphorylation, mitochondria's function, and activity of key tricarboxylic acid cycle enzymes. In contrast, glycolysis was increased in the unsuccessful attempt to extend cell survival despite mitochondrial dysfunction. The IE was associated with marked splenomegaly and low hepcidin levels, leading to iron accumulation in the liver, spleen, and bone marrow and the formation of ring sideroblasts. To investigate the potential of a gene therapy approach for XLSA, we developed a lentiviral vector (X-ALAS2-LV) to direct ALAS2 expression in erythroid cells. Infusion of bone marrow (BM) cells with 0.6 to 1.4 copies of the X-ALAS2-LV in Alas2-KOBM mice improved complete blood cell levels, tissue iron accumulation, and survival rates. These findings suggest our vector could be curative in patients with XLSA.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"98-113"},"PeriodicalIF":21.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11738033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How I treat ETP-ALL in children.","authors":"Ryan J Summers, David T Teachey, Stephen P Hunger","doi":"10.1182/blood.2023023155","DOIUrl":"10.1182/blood.2023023155","url":null,"abstract":"<p><strong>Abstract: </strong>Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a unique subtype of immature T-cell ALL that was initially associated with a dramatically inferior prognosis compared with non-ETP T-cell ALL (Not-ETP) when it was first described in 2009. Analyses of larger patient cohorts treated with more contemporary regimens, however, have shown minimal survival differences between ETP and Not-ETP. In this manuscript, we use representative cases to explore therapeutic advances and address common clinical questions regarding the management of children, adolescents, and young adults with ETP-ALL. We describe our recommended treatment approach for a child or adolescent with newly diagnosed ETP-ALL, with an emphasis on the prognostic significance of induction failure and detectable minimal residual disease and the role of hematopoietic stem cell transplant in first remission. We discuss the interplay between the ETP immunophenotype and genomic markers of immaturity in T-cell ALL. Finally, we review novel therapeutic approaches that should be considered when managing relapsed or refractory ETP-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"43-52"},"PeriodicalIF":21.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139746024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-risk MCL: recognition and treatment","authors":"Preetesh Jain, Michael Wang","doi":"10.1182/blood.2023022354","DOIUrl":"https://doi.org/10.1182/blood.2023022354","url":null,"abstract":"Significant progress in determining the molecular origins and resistance mechanisms of mantle cell lymphoma (MCL) has improved our understanding of the disease’s clinical diversity. These factors greatly impact the prognosis of patients with MCL. Given the dynamic alterations in MCL clones and disease evolution, it is crucial to recognize high-risk prognostic factors at diagnosis and relapse. Clinical factors include a high MCL International Prognostic Index score with a high Ki-67 proliferation index, early disease progression within 24 months of first-line treatment, &gt;3 previous lines of therapy at relapse, and an aggressive (blastoid or pleomorphic) histology. Molecular aberrations include dysregulated cyclin D1, an aberrant SOX11-CD70 axis, upregulated Musashi-2, <ce:italic>MYC</ce:italic> rearrangement, metabolic reprogramming, and epigenetic changes. Other factors that contribute to high-risk MCL include an immune-depleted microenvironment and clone adaptability with complex chromosomal anomalies and somatic mutations in <ce:italic>TP53, NSD2, CCND1, CDKN2A, BIRC3, SP140, KMT2D, NFkBIE, SMARCA4</ce:italic>, and <ce:italic>NOTCH2</ce:italic>. Ultra-high-risk MCL is indicated by the coexistence of multiple high-risk prognostic factors in the relapse setting and can portend very short progression-free survival. As MCL treatments advance toward cellular therapies, resistance to anti-CD19 chimeric antigen receptor T-cell therapy is also observed. These findings necessitate revisiting the prognostic impact of high-risk factors, current management strategies, new bi- and trispecific T-cell engagers, combination therapies, novel therapeutic targets, and next-generation clinical trials for patients with high-risk MCL. This article provides a comprehensive update on recognizing and managing high-risk MCL and encompass current practices and future directions.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"29 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA-approved therapies for chronic GVHD","authors":"Stephanie J. Lee, Robert Zeiser","doi":"10.1182/blood.2024026633","DOIUrl":"https://doi.org/10.1182/blood.2024026633","url":null,"abstract":"Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. cGVHD can affect multiple organs and reduces quality of life, and treatment can cause serious adverse effects. In the past 10 years, the drugs ibrutinib, ruxolitinib, belumosudil, and axatilimab were US Food and Drug Administration (FDA) approved for cGVHD. Here, we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA approval, and future directions for clinical research.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"75 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic and therapeutic implications of measurable residual disease levels during remission induction of childhood ALL.","authors":"Weina Zhang, Jiaoyang Cai, Xiang Wang, Yani Ma, Xiaofan Zhu, Jie Yu, Peifang Xiao, Ju Gao, Yongjun Fang, Changda Liang, Xue Li, Fen Zhou, Xiaowen Zhai, Xiaoxiao Xu, Xin Tian, Aiguo Liu, Ningling Wang, Jiashi Zhu, Lingzhen Wang, Frankie Wai Tsoi Cheng, Liangchun Yang, Ge Zhang, Cheng Cheng, Jun J Yang, Shuhong Shen, Chi-Kong Li, Benshang Li, Hua Jiang, Ching-Hon Pui","doi":"10.1182/blood.2024026381","DOIUrl":"https://doi.org/10.1182/blood.2024026381","url":null,"abstract":"<p><p>We evaluated the prognostic and therapeutic significance of measurable residual disease (MRD) during remission induction in pediatric acute lymphoblastic leukemia (ALL) patients. In the CCCG-ALL-2015 protocol, 7640 patients were categorized into low-, intermediate-, or high-risk groups based on clinical and genetic features. Final risk classification was determined by MRD assessed via flow cytometry on Days 19 and 46 of remission induction, with additional intensified chemotherapy for Day 19 MRD ≥1%. B-ALL patients with negative MRD (<0.01%) on Day 19 or Day 46 had significantly better 5-year event-free survival (EFS) than those with MRD 0.01-0.99%, who in turn had better EFS than patients with MRD ≥1%. Provisional low-risk patients with Day 19 MRD ≥1% but negative Day 46 MRD, reclassified as intermediate-risk, had comparable 5-year EFS to low-risk patients with Day 19 MRD 0.3-0.99% and negative Day 46 MRD (82.5% vs. 83.0%) and better EFS than provisional low-risk patients with MRD on both days (83.0% vs. 72.6%, P<0.001). Similarly, provisional intermediate-risk B-ALL patients with Day 19 MRD ≥1% but negative Day 46 MRD, who received additional therapy, had better 5-year EFS compared to those with Day 19 MRD between 0.3-0.99% (70.7% vs. 53.0%, P<0.001). Among low-risk patients with negative Day 46 MRD, those with negative Day 19 MRD had superior EFS compared to those with positive Day 19 MRD (91.7% vs. 86.1%, P<0.001). Optimal use of Day 19 MRD could improve individualized treatment and outcomes. Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reducing clinical trial eligibility barriers for patients with MDS: an icMDS position statement","authors":"Uma Borate, Kelly Pugh, Allyson Waller, Rina Li Welkie, Ying Huang, Jan Philipp Bewersdorf, Maximilian Stahl, Amy E. DeZern, Uwe Platzbecker, Mikkael A. Sekeres, Andrew H. Wei, Rena J. Buckstein, Gail J. Roboz, Michael R. Savona, Sanam Loghavi, Robert P. Hasserjian, Pierre Fenaux, David A. Sallman, Christopher S. Hourigan, Matteo Giovanni Della Porta, Stephen Nimer, Richard F. Little, Valeria Santini, Fabio Efficace, Justin Taylor, Guillermo Garcia-Manero, Olatoyosi Odenike, Tae Kon Kim, Stephanie Halene, Rami S. Komrokji, Elizabeth A. Griffiths, Peter L. Greenberg, Mina L. Xu, Zhuoer Xie, Rafael Bejar, Guillermo F. Sanz, Mrinal M. Patnaik, Maria Figueroa, Hetty E. Carraway, Omar Abdel-Wahab, Daniel Starczynowski, Eric Padron, Jacqueline Boultwood, Steven Gore, Naval G. Daver, Jane E. Churpek, Ravindra Majeti, John M. Bennett, Alan F. List, Andrew M. Brunner, Amer M. Zeidan","doi":"10.1182/blood.2023023717","DOIUrl":"https://doi.org/10.1182/blood.2023023717","url":null,"abstract":"Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on <ce:inter-ref xlink:href=\"http://ClinicalTrials.gov\" xlink:type=\"simple\">ClinicalTrials.gov</ce:inter-ref> from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"2 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma","authors":"Adrian Gottschlich, Ruth Grünmeier, Gordon Victor Hoffmann, Sayantan Nandi, Vladyslav Kavaka, Philipp Jie Müller, Jakob Jobst, Arman Öner, Rainer Kaiser, Jan Gärtig, Ignazio Piseddu, Stephanie Frenz-Wiessner, Savannah D. Fairley, Heiko Schulz, Veronika Igl, Thomas Alexander Janert, Lea di Fina, Maité Mulkers, Moritz Thomas, Daria Briukhovetska, Donjetë Simnica, Emanuele Carlini, Christina Angeliki Tsiverioti, Marcel P. Trefny, Theo Lorenzini, Florian Märkl, Pedro Mesquita, Ruben Brabenec, Thaddäus Strzalkowski, Sophia Stock, Stefanos Michaelides, Johannes Hellmuth, Martin Thelen, Sarah Reinke, Wolfram Klapper, Pascal Francois Gelebart, Leo Nicolai, Carsten Marr, Eduardo Beltrán, Remco T. A. Megens, Christoph Klein, Fanny Baran-Marszak, Andreas Rosenwald, Michael von Bergwelt-Baildon, Paul J. Bröckelmann, Stefan Endres, Sebastian Kobold","doi":"10.1182/blood.2023022197","DOIUrl":"https://doi.org/10.1182/blood.2023022197","url":null,"abstract":"The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and in-depth, single-cell–based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86–CTLA-4 as key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"84 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice","authors":"Maria Kauppi, Craig D. Hyland, Elizabeth M. Viney, Christine A. White, Carolyn A. de Graaf, AnneMarie E. Welch, Jumana Yousef, Laura F. Dagley, Samantha J. Emery-Corbin, Ladina Di Rago, Andrew J. Kueh, Marco J. Herold, Douglas J. Hilton, Jeffrey J. Babon, Nicos A. Nicola, Kira Behrens, Warren S. Alexander","doi":"10.1182/blood.2024025406","DOIUrl":"https://doi.org/10.1182/blood.2024025406","url":null,"abstract":"Cullin-5 (Cul5) coordinates the assembly of cullin-RING-E3 ubiquitin ligase complexes that include the suppressors of cytokine signaling (SOCS)-box–containing proteins. The SOCS-box proteins function to recruit specific substrates to the complex for ubiquitination and degradation. In hematopoiesis, SOCS-box proteins are best known for regulating the actions of cytokines that utilize the JAK-STAT signaling pathway. However, the roles of most SOCS-box proteins have not been studied in physiological contexts and any actions for Cul5/SOCS complexes in signaling by several hematopoietic cytokines, including thrombopoietin (TPO) and interleukin-3 (IL-3), remain unknown. To define additional potential roles for Cul5/SOCS complexes, we generated mice lacking Cul5 in hematopoiesis; the absence of Cul5 is predicted to impair the SOCS-box–dependent actions of all proteins that contain this motif. Here, we show that Cul5-deficient mice develop excess megakaryopoiesis and thrombocytosis revealing a novel mechanism of negative regulation of megakaryocyte-committed stem cells, a distinct population within the hematopoietic stem cell pool that have been shown to rapidly, perhaps directly, generate megakaryocytes, and which are produced in excess in the absence of Cul5. Cul5-deficient megakaryopoiesis is distinctive in being largely independent of TPO/Mpl and involves signaling via the β-common and/or β-IL-3 receptors, with evidence of deregulated responses to IL-3. This process is independent of the interferon-α/β receptor, previously implicated in inflammation-induced activation of stem-like megakaryocyte progenitor cells.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"28 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNTT-mediated DNA damage response drives inotuzumab ozogamicin resistance in B-cell acute lymphoblastic leukemia","authors":"Carolin S. Escherich, Takaya Moriyama, Zhenhua Li, Yu-Chih Hsiao, Wenjian Yang, Yizhen Li, Noemi Reyes, Megan Walker, Amit Budhraja, Sheetal Bhatara, Ernesto Diaz-Flores, Wendy Stock, Elisabeth Paietta, Marina Y. Konopleva, Steven M. Kornblau, Mark R. Litzow, Hiroto Inaba, Ching-Hon Pui, Joseph T. Opferman, Mignon L. Loh, Jiyang Yu, Maureen M. O’Brien, William E. Evans, Jun J. Yang","doi":"10.1182/blood.2024026085","DOIUrl":"https://doi.org/10.1182/blood.2024026085","url":null,"abstract":"Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of <ce:italic>DNTT</ce:italic> attenuated InO–induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with <ce:italic>DNTT</ce:italic> expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the COG trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"24 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases","authors":"Apeksha Singh, Jennifer J. Chia, Dinesh S. Rao, Alexander Hoffmann","doi":"10.1182/blood.2024025598","DOIUrl":"https://doi.org/10.1182/blood.2024025598","url":null,"abstract":"Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) among hematopoietic stem and progenitor cells (HSPCs). Although hematopoietic stem cell (HSC) differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB<ce:sup loc=\"post\">−</ce:sup> (<ce:italic>Nfkbia</ce:italic><ce:sup loc=\"post\">+/−</ce:sup><ce:italic>Nfkbib</ce:italic><ce:sup loc=\"post\">−/−</ce:sup><ce:italic>Nfkbie</ce:italic><ce:sup loc=\"post\">−/−</ce:sup>) mouse model of inflammation with elevated NFκB activity, which reveals increased myeloid-biased MPPs. We interpreted these data with differential equation models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB<ce:sup loc=\"post\">−</ce:sup> and wild-type HSPCs to track the continuous differentiation trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification among HSCs but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation trajectories supported increased proliferation among these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB<ce:sup loc=\"post\">−</ce:sup> recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice and human patients with myeloid neoplasm. These analyses identified the same myeloid-primed progenitor expansion as in the IκB<ce:sup loc=\"post\">−</ce:sup> models, suggesting that it is a common feature across different settings of myeloid bias.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"35 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}