{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:10:46Z","timestamp":1790647846930,"version":"4.1.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K01DK121733"],"award-info":[{"award-number":["K01DK121733"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-22-1-0805"],"award-info":[{"award-number":["W81XWH-22-1-0805"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008884","name":"Edward P. Evans Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014084","name":"Vera and Joseph Dresner Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014084","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    BM resulted in hematopoietic stem\/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.\n                  <\/jats:p>","DOI":"10.1038\/s41375-024-02304-9","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T15:20:25Z","timestamp":1719501625000},"page":"1787-1798","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy"],"prefix":"10.1038","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6733-3190","authenticated-orcid":false,"given":"Emily","family":"Stepanchick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2229-3134","authenticated-orcid":false,"given":"Analise M.","family":"Sulentic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-962X","authenticated-orcid":false,"given":"Kwangmin","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Hueneman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5771-7462","authenticated-orcid":false,"given":"Daniel T.","family":"Starczynowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0133-8949","authenticated-orcid":false,"given":"Timothy M.","family":"Chlon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,27]]},"reference":[{"key":"2304_CR1","doi-asserted-by":"crossref","unstructured":"Makishima H, Saiki R, Nannya Y, Korotev SC, Gurnari C, Takeda J, et al. Germline DDX41 mutations define a unique subtype of myeloid neoplasms. Blood. 2022;141:534\u201349.","DOI":"10.1182\/blood.2022018221"},{"key":"2304_CR2","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1182\/blood.2021015135","volume":"140","author":"P Li","year":"2022","unstructured":"Li P, Brown S, Williams M, White T, Xie W, Cui W, et al. The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood. 2022;140:716\u201355.","journal-title":"Blood"},{"key":"2304_CR3","doi-asserted-by":"crossref","unstructured":"Choi EJ, Cho YU, Hur EH, Jang S, Kim N, Park HS, et al. Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia. Haematologica. 2021;107:510\u20138.","DOI":"10.3324\/haematol.2020.270553"},{"key":"2304_CR4","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1182\/blood.2019000909","volume":"134","author":"M S\u00e9bert","year":"2019","unstructured":"S\u00e9bert M, Passet M, Raimbault A, Rahm\u00e9 R, Raffoux E, Sicre de Fontbrune F, et al. Germline DDX41 mutations define a significant entity within adult MDS\/AML patients. Blood. 2019;134:1441\u20134.","journal-title":"Blood"},{"key":"2304_CR5","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1002\/ajh.25486","volume":"94","author":"AE Quesada","year":"2019","unstructured":"Quesada AE, Routbort MJ, DiNardo CD, Bueso-Ramos CE, Kanagal-Shamanna R, Khoury JD, et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol. 2019;94:757\u201366.","journal-title":"Am J Hematol"},{"key":"2304_CR6","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.ccell.2015.03.017","volume":"27","author":"C Polprasert","year":"2015","unstructured":"Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell. 2015;27:658\u201370.","journal-title":"Cancer Cell"},{"key":"2304_CR7","doi-asserted-by":"crossref","unstructured":"Badar T, Chlon T. Germline and somatic defects in ddx41 and its impact on myeloid neoplasms. Curr Hematol Malig Rep. 2022;17:113\u201320.","DOI":"10.1007\/s11899-022-00667-3"},{"key":"2304_CR8","doi-asserted-by":"crossref","unstructured":"Chlon TM, Stepanchick E, Hershberger CE, Daniels NJ, Hueneman KM, Kuenzi Davis A, et al. Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia. Cell Stem Cell. 2021;28:1966\u201381.","DOI":"10.1016\/j.stem.2021.08.004"},{"key":"2304_CR9","doi-asserted-by":"crossref","unstructured":"Qu S, Li B, Qin T, Xu Z, Pan L, Hu N, et al. Molecular and clinical features of myeloid neoplasms with somatic DDX41 mutations. Br J Haematol. 2020;192:1006\u201310.","DOI":"10.1111\/bjh.16668"},{"key":"2304_CR10","doi-asserted-by":"crossref","unstructured":"Bataller A, Loghavi S, Gerstein Y, Bazinet A, Sasaki K, Chien KS, et al. Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants. Am J Hematol. 2023;98:1780\u201390.","DOI":"10.1002\/ajh.27070"},{"key":"2304_CR11","doi-asserted-by":"publisher","first-page":"2736","DOI":"10.1002\/1873-3468.14487","volume":"596","author":"JT Weinreb","year":"2022","unstructured":"Weinreb JT, Bowman TV. Clinical and mechanistic insights into the roles of DDX41 in haematological malignancies. FEBS Lett. 2022;596:2736\u201345.","journal-title":"FEBS Lett"},{"key":"2304_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0960-9822(00)00002-6","volume":"4","author":"T Jacks","year":"1994","unstructured":"Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, et al. Tumor spectrum analysis in p53-mutant mice. Curr Biol. 1994;4:1\u20137.","journal-title":"Curr Biol"},{"key":"2304_CR13","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/s41596-018-0100-z","volume":"14","author":"L Hidalgo San Jose","year":"2019","unstructured":"Hidalgo San Jose L, Signer RAJ. Cell-type-specific quantification of protein synthesis in vivo. Nat Protoc. 2019;14:441\u201360.","journal-title":"Nat Protoc"},{"key":"2304_CR14","doi-asserted-by":"publisher","first-page":"8737","DOI":"10.1073\/pnas.0701829104","volume":"104","author":"J Shuga","year":"2007","unstructured":"Shuga J, Zhang J, Samson LD, Lodish HF, Griffith LG. In vitro erythropoiesis from bone marrow-derived progenitors provides a physiological assay for toxic and mutagenic compounds. Proc Natl Acad Sci. 2007;104:8737\u201342.","journal-title":"Proc Natl Acad Sci"},{"key":"2304_CR15","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-019-5548-x","volume":"20","author":"K Choi","year":"2019","unstructured":"Choi K, Ratner N. iGEAK: an interactive gene expression analysis kit for seamless workflow using the R\/shiny platform. BMC Genomics. 2019;20:177.","journal-title":"BMC Genomics"},{"key":"2304_CR16","doi-asserted-by":"publisher","first-page":"W755","DOI":"10.1093\/nar\/gkq405","volume":"38","author":"D Emig","year":"2010","unstructured":"Emig D, Salomonis N, Baumbach J, Lengauer T, Conklin BR, Albrecht M. AltAnalyze and DomainGraph: analyzing and visualizing exon expression data. Nucleic Acids Res. 2010;38:W755\u2013762.","journal-title":"Nucleic Acids Res"},{"key":"2304_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14049","volume":"8","author":"GXY Zheng","year":"2017","unstructured":"Zheng GXY, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017;8:14049.","journal-title":"Nat Commun"},{"key":"2304_CR18","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573\u20133587.e3529.","journal-title":"Cell"},{"key":"2304_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.","journal-title":"Genome Biol"},{"key":"2304_CR20","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nbt.4235","volume":"36","author":"R Poplin","year":"2018","unstructured":"Poplin R, Chang P-C, Alexander D, Schwartz S, Colthurst T, Ku A, et al. A universal SNP and small-indel variant caller using deep neural networks. Nat Biotechnol. 2018;36:983\u20137.","journal-title":"Nat Biotechnol"},{"key":"2304_CR21","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","volume":"6","author":"P Cingolani","year":"2012","unstructured":"Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly. 2012;6:80\u201392.","journal-title":"Fly"},{"key":"2304_CR22","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.stemcr.2022.02.010","volume":"17","author":"J Ma","year":"2022","unstructured":"Ma J, Mahmud N, Bosland MC, Ross SR. DDX41 is needed for pre- and postnatal hematopoietic stem cell differentiation in mice. Stem Cell Rep. 2022;17:879\u201393. 2022\/04\/12\/","journal-title":"Stem Cell Rep"},{"key":"2304_CR23","doi-asserted-by":"crossref","unstructured":"Harris BD, Lee J, Gillis J. A Meta-Analytic Single-Cell Atlas of Mouse Bone Marrow Hematopoietic Development. bioRxiv. 2021. https:\/\/www.biorxiv.org\/content\/10.1101\/2021.08.12.456098v1.","DOI":"10.1101\/2021.08.12.456098"},{"key":"2304_CR24","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","volume":"44","author":"MV Kuleshov","year":"2016","unstructured":"Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90\u201397.","journal-title":"Nucleic Acids Res"},{"key":"2304_CR25","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.1182\/blood-2010-07-295238","volume":"117","author":"S Dutt","year":"2011","unstructured":"Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, Megerdichian C, et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood. 2011;117:2567\u201376.","journal-title":"Blood"},{"key":"2304_CR26","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1128\/MCB.01307-06","volume":"27","author":"MS Lindstro\u00f6m","year":"2007","unstructured":"Lindstro\u00f6m MS, Jin A, Deisenroth C, White Wolf G, Zhang Y. Cancer-Associated Mutations in the MDM2 Zinc Finger Domain Disrupt Ribosomal Protein Interaction and Attenuate MDM2-Induced p53 Degradation. Mol Cell Biol. 2007;27:1056\u201368.","journal-title":"Mol Cell Biol"},{"key":"2304_CR27","doi-asserted-by":"publisher","first-page":"e0152263","DOI":"10.1371\/journal.pone.0152263","volume":"11","author":"T Kamio","year":"2016","unstructured":"Kamio T, Gu B-w, Olson TS, Zhang Y, Mason PJ, Bessler M. Mice with a Mutation in the Mdm2 Gene That Interferes with MDM2\/Ribosomal Protein Binding Develop a Defect in Erythropoiesis. PLOS ONE. 2016;11:e0152263.","journal-title":"PLOS ONE"},{"key":"2304_CR28","doi-asserted-by":"publisher","first-page":"644","DOI":"10.3324\/haematol.2020.257246","volume":"107","author":"JT Weinreb","year":"2022","unstructured":"Weinreb JT, Gupta V, Sharvit E, Weil R, Bowman TV. Ddx41 inhibition of DNA damage signaling permits erythroid progenitor expansion in zebrafish. Haematologica. 2022;107:644\u201354.","journal-title":"Haematologica"},{"key":"2304_CR29","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.devcel.2021.02.006","volume":"56","author":"JT Weinreb","year":"2021","unstructured":"Weinreb JT, Ghazale N, Pradhan K, Gupta V, Potts KS, Tricomi B, et al. Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production. Dev Cell. 2021;56:627\u2013.e625.","journal-title":"Dev Cell"},{"key":"2304_CR30","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.exphem.2016.04.017","volume":"44","author":"M Kadono","year":"2016","unstructured":"Kadono M, Kanai A, Nagamachi A, Shinriki S, Kawata J, Iwato K, et al. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia. Exp Hematol. 2016;44:745\u2013.e744.","journal-title":"Exp Hematol"},{"key":"2304_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27530-y","volume":"12","author":"T Mosler","year":"2021","unstructured":"Mosler T, Conte F, Longo GMC, Mikicic I, Kreim N, M\u00f6ckel MM, et al. R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability. Nat Commun. 2021;12:7314.","journal-title":"Nat Commun"},{"key":"2304_CR32","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1182\/blood.2023020209","volume":"142","author":"S Cheloor Kovilakam","year":"2023","unstructured":"Cheloor Kovilakam S, Gu M, Dunn WG, Marando L, Barcena C, Nik-Zainal S, et al. Prevalence and significance of DDX41 gene variants in the general population. Blood. 2023;142:1185\u201392.","journal-title":"Blood"},{"key":"2304_CR33","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1182\/blood-2018-03-784116","volume":"132","author":"L Barreyro","year":"2018","unstructured":"Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132:1553\u201360.","journal-title":"Blood"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02304-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02304-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02304-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T11:03:11Z","timestamp":1722250991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02304-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,27]]},"references-count":33,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["2304"],"URL":"https:\/\/doi.org\/10.1038\/s41375-024-02304-9","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,27]]},"assertion":[{"value":"20 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"DTS serves on the scientific advisory board at Kurome Therapeutics and is a consultant for and\/or received funding from Kurome Therapeutics, Captor Therapeutics, Treeline Biosciences, and Tolero Therapeutics. DTS has equity in Kurome Therapeutics. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}