<i>Prdm15</i> deficiency perturbs hematopoietic stem and progenitor cell homeostasis

Qiwen Dong; Weiwei Xiao; Junsong Huang; Zheng Sun; Min Liang; Mengjiao Wang; Qingqing Wang; Xinlan Zong; Anzi Li; Yan Wang; Zhongsheng Sun

doi:10.1016/j.jgg.2026.07.009

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Prdm15 deficiency perturbs hematopoietic stem and progenitor cell homeostasis

doi: 10.1016/j.jgg.2026.07.009

a. Beijing Children’s Hospital, National Center for Children’s Health, Beijing 100045, China;
b. Interdisciplinary Science Center, State Key Laboratory of Animal Biodiversity Conservation and Integrated Pest Management, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
c. College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China

Funds:

D Program of China (2025YFA1309200).

We sincerely thank Ernesto Guccione for generously providing antibodies and scientific support. This work was supported by the National Natural Science Foundation of China (32070590 and 32470630), the National Key R&

Received Date: 2026-02-15
Accepted Date: 2026-07-21
Rev Recd Date: 2026-07-20

Available Online: 2026-07-29

Abstract

Abstract

The maintenance of homeostasis in hematopoietic stem and progenitor cells (HSPCs) is essential for the proper development of the entire hematopoietic system. However, the mechanisms underlying this regulatory equilibrium remain elusive. Here, we report that Prdm15 deficiency in HSPCs induces the accumulation of immature hematopoietic stem cells in mice. A series of transplantation assays shows that these cells display impaired reconstitution capacity and competitive fitness, which are associated with abnormal differentiation trajectories and transcriptional alterations identified by single-cell RNA sequencing. Mechanistically, integrated multi-omics analyses including ATAC-seq and CUT&Tag sequencing of HSPCs indicate that Prdm15 deficiency induces significant transcriptional and epigenetic alterations, particularly affecting the methyltransferase KMT2C and altering H3K4me1 and H3K27ac modifications at the promoters of hematopoietic developmental genes. Collectively, our findings establish PRDM15 as a critical epigenetic regulator of HSPCs, offering valuable insights into the molecular mechanisms underlying hematopoietic homeostasis.
- Hematopoietic stem and progenitor cells,
- Hematopoietic homeostasis,
- Cell differentiation,
- Epigenetics,
- PRDM15

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Antonchuk, J., Sauvageau, G., Humphries, R.K., 2002. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 109, 39-45.

Baccin, C., Al-Sabah, J., Velten, L., Helbling, P.M., Grunschlager, F., Hernandez-Malmierca, P., Nombela-Arrieta, C., Steinmetz, L.M., Trumpp, A., Haas, S., 2020. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat. Cell. Biol. 22, 38-48.

Baldridge, M.T., King, K.Y., Boles, N.C., Weksberg, D.C., Goodell, M.A., 2010. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature 465, 793-797.

Beerman, I., Bock, C., Garrison, B.S., Smith, Z.D., Gu, H., Meissner, A., Rossi, D.J., 2013. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12, 413-425.

Boi, M., Rinaldi, A., Kwee, I., Bonetti, P., Todaro, M., Tabbo, F., Piva, R., Rancoita, P.M., Matolcsy, A., Timar, B., et al., 2013. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood 122, 2683-2693.

Broske, A.M., Vockentanz, L., Kharazi, S., Huska, M.R., Mancini, E., Scheller, M., Kuhl, C., Enns, A., Prinz, M., Jaenisch, R., et al., 2009. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat. Genet. 41, 1207-1215.

Cao, W., Xie, Y., Cai, L., Wang, M., Chen, Z., Wang, Z., Xv, J., Wang, Y., Li, R., Liu, X., et al., 2024. Pan-cancer analysis on the role of KMT2C expression in tumor progression and immunotherapy. Oncol. Lett. 28, 444.

Cenik, B.K., Shilatifard, A., 2021. COMPASS and SWI/SNF complexes in development and disease. Nat. Rev. Genet. 22, 38-58.

Chen, C., Liu, Y., Rappaport, A.R., Kitzing, T., Schultz, N., Zhao, Z., Shroff, A.S., Dickins, R.A., Vakoc, C.R., Bradner, J.E., et al., 2014. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25, 652-665.

Chen, F., Lu, Y., Xu, Y., Chen, N., Yang, L., Zhong, X., Zeng, H., Liu, Y., Chen, Z., Zhang, Q., et al., 2024. Trim47 prevents hematopoietic stem cell exhaustion during stress by regulating MAVS-mediated innate immune pathway. Nat. Commun. 15, 6787.

Chen, R., Okeyo-Owuor, T., Patel, R.M., Casey, E.B., Cluster, A.S., Yang, W., Magee, J.A., 2021. Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy. Cell Rep. 34, 108751.

Chen, T., Chen, X., Zhang, S., Zhu, J., Tang, B., Wang, A., Dong, L., Zhang, Z., Yu, C., Sun, Y., et al., 2021. The genome sequence archive family: toward explosive data growth and diverse data types. Genomics Proteomics Bioinformatics 19, 578-583.

CNCB-NGDC Members and Partners, 2025. Database resources of the national genomics data center, China national center for bioinformation in 2025. Nucleic Acids Res 53, D30-D44.

Cullen, S.M., Mayle, A., Rossi, L., Goodell, M.A., 2014. Hematopoietic stem cell development: an epigenetic journey. Curr. Top. Dev. Biol. 107, 39-75.

Dettman, E.J., Simko, S.J., Ayanga, B., Carofino, B.L., Margolin, J.F., Morse, H.C., 3rd, Justice, M.J., 2011. Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors. Oncogene 30, 2859-2873.

Di Tullio, F., Schwarz, M., Zorgati, H., Mzoughi, S., Guccione, E., 2022. The duality of PRDM proteins: epigenetic and structural perspectives. FEBS J. 289, 1256-1275.

Dzierzak, E., Bigas, A., 2018. Blood development: hematopoietic stem cell dependence and independence. Cell Stem Cell 22, 639-651.

Feng, Y., Yang, Y., Ortega, M.M., Copeland, J.N., Zhang, M., Jacob, J.B., Fields, T.A., Vivian, J.L., Fields, P.E., 2010. Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood 116, 4483-4491.

Fog, C.K., Galli, G.G., Lund, A.H., 2012. PRDM proteins: important players in differentiation and disease. Bioessays 34, 50-60.

Glass, C., Wilson, M., Gonzalez, R., Zhang, Y., Perkins, A.S., 2014. The role of EVI1 in myeloid malignancies. Blood Cells Mol. Dis. 53, 67-76.

Gudmundsson, K.O., Nguyen, N., Oakley, K., Han, Y., Gudmundsdottir, B., Liu, P., Tessarollo, L., Jenkins, N.A., Copeland, N.G., Du, Y., 2020. Prdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence. Proc. Natl. Acad. Sci. U. S. A. 117, 31945-31953.

Hirai, H., Zhang, P., Dayaram, T., Hetherington, C.J., Mizuno, S., Imanishi, J., Akashi, K., Tenen, D.G., 2006. C/EBPbeta is required for 'emergency' granulopoiesis. Nat. Immunol. 7, 732-739.

Itoh-Nakadai, A., Matsumoto, M., Kato, H., Sasaki, J., Uehara, Y., Sato, Y., Ebina-Shibuya, R., Morooka, M., Funayama, R., Nakayama, K., et al., 2017. A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors. Cell Rep. 18, 2401-2414.

Iwama, A., Oguro, H., Negishi, M., Kato, Y., Morita, Y., Tsukui, H., Ema, H., Kamijo, T., Katoh-Fukui, Y., Koseki, H., et al., 2004. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21, 843-851.

Jiao, Y., Lv, Y., Liu, M., Liu, Y., Han, M., Xiong, X., Zhou, H., Zhong, J., Kang, X., Su, W., 2024. The modification role and tumor association with a methyltransferase: KMT2C. Front Immunol. 15, 1444923.

Kanagal-Shamanna, R., Beck, D.B., Calvo, K.R., 2024. Clonal hematopoiesis, inflammation, and hematologic malignancy. Annu. Rev. Pathol. 19, 479-506.

Komic, H., Schmachtel, T., Simoes, C., Kulp, M., Yu, W., Jolly, A., Nilsson, M.S., Gonzalez, C., Prosper, F., Bonig, H., et al., 2025. Continuous map of early hematopoietic stem cell differentiation across human lifetime. Nat. Commun. 16, 2287.

Lee, J., Saha, P.K., Yang, Q.H., Lee, S., Park, J.Y., Suh, Y., Lee, S.K., Chan, L., Roeder, R.G., Lee, J.W., 2008. Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl. Acad. Sci. U. S. A. 105, 19229-19234.

Levavasseur, F., Oussous, S., Framarini, A., Boussaid, I., Gou, P., Tuerdi, Z., Boueya, I.L., Hoffner, H., De Almeida, M., Gall, M.L., et al., 2025. FOXP1 contributes to murine hematopoietic stem cell functionality. Exp. Hematol. 149, 104815.

Li, D., Zhang, Y., Qiu, Q., Wang, J., Zhao, X., Jiao, B., Zhang, X., Yu, S., Xu, P., Dan, Y., et al., 2021. IRF8 impacts self-renewal of hematopoietic stem cells by regulating TLR9 signaling pathway of innate immune cells. Adv. Sci. (Weinh) 8, e2101031.

Liu, Y.X., Dong, X., Gong, F., Su, N., Li, S.B., Zhang, H.T., Liu, J.L., Xue, J.H., Ji, S.P., Zhang, Z.W., 2015. Promotion of erythropoietic differentiation in hematopoietic stem cells by SOCS3 knock-down. PLoS ONE 10, e0135259.

Mombaerts, P., Iacomini, J., Johnson, R.S., Herrup, K., Tonegawa, S., Papaioannou, V.E., 1992. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869-877.

Mzoughi, S., Di Tullio, F., Low, D.H.P., Motofeanu, C.M., Ong, S.L.M., Wollmann, H., Wun, C.M., Kruszka, P., Muenke, M., Hildebrandt, F., et al., 2020a. PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly. Sci. Adv. 6, eaax9852.

Mzoughi, S., Fong, J.Y., Papadopoli, D., Koh, C.M., Hulea, L., Pigini, P., Di Tullio, F., Andreacchio, G., Hoppe, M.M., Wollmann, H., et al., 2020b. PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis. Nat. Commun. 11, 3520.

Mzoughi, S., Tan, Y.X., Low, D., Guccione, E., 2016. The role of PRDMs in cancer: one family, two sides. Curr. Opin. Genet. Dev. 36, 83-91.

Mzoughi, S., Zhang, J., Hequet, D., Teo, S.X., Fang, H., Xing, Q.R., Bezzi, M., Seah, M.K.Y., Ong, S.L.M., Shin, E.M., et al., 2017. PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling. Nat. Genet. 49, 1354-1363.

Oh, I.H., Humphries, R.K., 2012. Concise review: multidimensional regulation of the hematopoietic stem cell state. Stem Cells 30, 82-88.

Osawa, M., Hanada, K., Hamada, H., Nakauchi, H., 1996. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242-245.

Raaijmakers, M.H., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J.A., Ebert, B.L., Al-Shahrour, F., Hasserjian, R.P., Scadden, E.O., et al., 2010. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852-857.

Radomska, H.S., Huettner, C.S., Zhang, P., Cheng, T., Scadden, D.T., Tenen, D.G., 1998. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol. Cell. Biol. 18, 4301-4314.

Reid, A.G., Nacheva, E.P., 2004. A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion. Leukemia 18, 178-180.

Romero-Garcia, R., Gomez-Jaramillo, L., Mateos, R.M., Jimenez-Gomez, G., Pedreno-Horrillo, N., Foncubierta, E., Rodriguez-Gutierrez, J.F., Garzon, S., Mora-Lopez, F., Rodriguez, C., et al., 2020. Differential epigenetic regulation between the alternative promoters, PRDM1α and PRDM1β, of the tumour suppressor gene PRDM1 in human multiple myeloma cells. Sci. Rep. 10, 15899.

Rossi, L., Lin, K.K., Boles, N.C., Yang, L., King, K.Y., Jeong, M., Mayle, A., Goodell, M.A., 2012. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell 11, 302-317.

Scott, E.W., Simon, M.C., Anastasi, J., Singh, H., 1994. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265, 1573-1577.

Shadat, N.M., Koide, N., Khuda, II, Dagvadorj, J., Tumurkhuu, G., Naiki, Y., Komatsu, T., Yoshida, T., Yokochi, T., 2010. Retinoblastoma protein-interacting zinc finger 1 (RIZ1) regulates the proliferation of monocytic leukemia cells via activation of p53. Cancer Invest. 28, 806-812.

Shibuya, K., Kudoh, J., Okui, M., Shimizu, N., 2005. Identification of a novel zinc finger protein gene (ZNF298) in the GAP2 of human chromosome 21q. Biochem. Biophys. Res. Commun. 332, 557-568.

Shing, D.C., Trubia, M., Marchesi, F., Radaelli, E., Belloni, E., Tapinassi, C., Scanziani, E., Mecucci, C., Crescenzi, B., Lahortiga, I., et al., 2007. Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice. J. Clin. Invest. 117, 3696-3707.

Skvortsova, K., Iovino, N., Bogdanovic, O., 2018. Functions and mechanisms of epigenetic inheritance in animals. Nat. Rev. Mol. Cell Biol. 19, 774-790.

Suzukawa, K., Parganas, E., Gajjar, A., Abe, T., Takahashi, S., Tani, K., Asano, S., Asou, H., Kamada, N., Yokota, J., et al., 1994. Identification of a breakpoint cluster region 3' of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26). Blood 84, 2681-2688.

Takizawa, H., Fritsch, K., Kovtonyuk, L.V., Saito, Y., Yakkala, C., Jacobs, K., Ahuja, A.K., Lopes, M., Hausmann, A., Hardt, W.D., et al., 2017. Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes proliferation but reduces competitive fitness. Cell Stem Cell 21, 225-240.

Trougakos, I.P., Pawelec, G., Tzavelas, C., Ntouroupi, T., Gonos, E.S., 2006. Clusterin/Apolipoprotein J up-regulation after zinc exposure, replicative senescence or differentiation of human haematopoietic cells. Biogerontology 7, 375-382.

Uchida, N., Friera, A.M., He, D., Reitsma, M.J., Tsukamoto, A.S., Weissman, I.L., 1997. Hydroxyurea can be used to increase mouse c-kit+Thy-1.1loLin-/loSca-1+ hematopoietic cell number and frequency in cell cycle in vivo. Blood 90, 4354-4362.

Wang, H., Diao, D., Shi, Z., Zhu, X., Gao, Y., Gao, S., Liu, X., Wu, Y., Rudolph, K.L., Liu, G., et al., 2016. SIRT6 controls hematopoietic stem cell homeostasis through epigenetic regulation of Wnt signaling. Cell Stem Cell 18, 495-507.

Wang, H.C., Chen, R., Yang, W., Li, Y., Muthukumar, R., Patel, R.M., Casey, E.B., Denby, E., Magee, J.A., 2024. Kmt2c restricts G-CSF-driven HSC mobilization and granulocyte production in a methyltransferase-independent manner. Cell Rep. 43, 114542.

Wang, J.H., Avitahl, N., Cariappa, A., Friedrich, C., Ikeda, T., Renold, A., Andrikopoulos, K., Liang, L., Pillai, S., Morgan, B.A., et al., 1998. Aiolos regulates B cell activation and maturation to effector state. Immunity 9, 543-553.

Wang, L.H., Aberin, M.A.E., Wu, S., Wang, S.P., 2021. The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape. Biochem. Soc. Trans. 49, 1041-1054.

Xie, X., Liu, M., Zhang, Y., Wang, B., Zhu, C., Wang, C., Li, Q., Huo, Y., Guo, J., Xu, C., et al., 2021. Single-cell transcriptomic landscape of human blood cells. Natl. Sci. Rev. 8, nwaa180.

Yan, J., Chen, S.A., Local, A., Liu, T., Qiu, Y., Dorighi, K.M., Preissl, S., Rivera, C.M., Wang, C., Ye, Z., et al., 2018. Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell Res. 28, 387.

Zhang, Y., Stehling-Sun, S., Lezon-Geyda, K., Juneja, S.C., Coillard, L., Chatterjee, G., Wuertzer, C.A., Camargo, F., Perkins, A.S., 2011. PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. Blood 118, 3853-3861.

Zhao, X., Bartholdy, B., Yamamoto, Y., Evans, E.K., Alberich-Jorda, M., Staber, P.B., Benoukraf, T., Zhang, P., Zhang, J., Trinh, B.Q., et al., 2022. PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development. Commun. Biol. 5, 961.

Zou, P., Yoshihara, H., Hosokawa, K., Tai, I., Shinmyozu, K., Tsukahara, F., Maru, Y., Nakayama, K., Nakayama, K.I., Suda, T., 2011. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 9, 247-261.

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