{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:29:16Z","timestamp":1785421756178,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,30]]},"group-title":"Immunology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R21AI178249"],"award-info":[{"award-number":["R21AI178249"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["PF-25-1435117-01-PFCBI"],"award-info":[{"award-number":["PF-25-1435117-01-PFCBI"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Loss of function mutation in the human\n                  <jats:italic>DPP9<\/jats:italic>\n                  gene causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia and patients require bone marrow transplantation, but the mechanism of cell loss is unclear since\n                  <jats:italic>Dpp9<\/jats:italic>\n                  mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34\n                  <jats:sup>+<\/jats:sup>\n                  hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human\n                  <jats:italic>DPP9<\/jats:italic>\n                  deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However,\n                  <jats:italic>DPP9<\/jats:italic>\n                  deletion led to little transcriptional changes suggesting post-transcriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to the activation of the CARD8 inflammasome resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.\n                <\/jats:p>","DOI":"10.64898\/2026.06.27.735024","type":"posted-content","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:47:57Z","timestamp":1782845277000},"source":"Crossref","is-referenced-by-count":0,"title":["Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4508-3973","authenticated-orcid":false,"given":"Tianli","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Richard","family":"Brewer","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1578-8024","authenticated-orcid":false,"given":"Maximilian","family":"Carlino","sequence":"additional","affiliation":[{"name":"Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA"},{"name":"Department of Pathology and Molecular Medicine, Yale University, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailin","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamato","family":"Takabe","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale University, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly Nicole","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin H.","family":"Nassar","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Division of Medical Oncology, Yale Cancer Center, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiankun","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0993-5956","authenticated-orcid":false,"given":"Kristen","family":"Brennad","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, CT, USA"},{"name":"Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Shan","sequence":"additional","affiliation":[{"name":"Institute of Human Immunology, Shenzhen Medical Academy of Research and Translation, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esen","family":"Sefik","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane S.","family":"Krause","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Department of Laboratory Medicine, Yale University, New Haven, CT, USA"},{"name":"Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Flavell","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070308400903000_2026.06.27.735024v1.1","doi-asserted-by":"crossref","unstructured":"Harapas CR , et al. 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