GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome
Abstract GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing...
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Nature Publishing Group
2025-01-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-025-01213-z |
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| author | Laetitia Largeaud Vincent Fregona Laura A. Jamrog Camille Hamelle Stéphanie Dufrechou Naïs Prade Esmaa Sellam Pauline Enfedaque Manon Bayet Sylvie Hébrard Mathieu Bouttier Christine Didier Bastien Gerby Eric Delabesse Marlène Pasquet Cyril Broccardo |
| author_facet | Laetitia Largeaud Vincent Fregona Laura A. Jamrog Camille Hamelle Stéphanie Dufrechou Naïs Prade Esmaa Sellam Pauline Enfedaque Manon Bayet Sylvie Hébrard Mathieu Bouttier Christine Didier Bastien Gerby Eric Delabesse Marlène Pasquet Cyril Broccardo |
| author_sort | Laetitia Largeaud |
| collection | DOAJ |
| description | Abstract GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing molecular and functional approaches, we investigated the mutation’s impact on hematopoiesis, revealing significant alterations in the hematopoietic stem and progenitor (HSPC) compartment in young age. These include increased LT-HSC numbers, reduced self-renewal potential, and impaired response to acute inflammatory stimuli. The mature HSPC compartment was primarily affected at the CMP sub-population level. In the mutant LT-HSC population, we identified an aberrant subpopulation strongly expressing CD150, resembling aging, but occurring prematurely. This population showed hyporesponsiveness, accumulated over time, and exhibited allele-specific expression (ASE) favoring the mutated Gata2 allele, also observed in GATA2 mutated patients. Our findings reveal the detrimental impact of a Gata2 recurrent missense mutation on the HSC compartment contributing to its functional decline. Defects in the CMP mature compartment, along with the inflammatory molecular signature, explain the loss of heterogeneity in HPC compartment observed in patients. Finally, our study provides a valuable model that recapitulates the ASE-related pathology observed in GATA2 deficiency, shedding light on the mechanisms contributing to the disease’s natural progression. |
| format | Article |
| id | doaj-art-42f687611fe64b74816593d84d6779f8 |
| institution | Kabale University |
| issn | 2044-5385 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-42f687611fe64b74816593d84d6779f82025-02-02T12:09:29ZengNature Publishing GroupBlood Cancer Journal2044-53852025-01-0115111310.1038/s41408-025-01213-zGATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndromeLaetitia Largeaud0Vincent Fregona1Laura A. Jamrog2Camille Hamelle3Stéphanie Dufrechou4Naïs Prade5Esmaa Sellam6Pauline Enfedaque7Manon Bayet8Sylvie Hébrard9Mathieu Bouttier10Christine Didier11Bastien Gerby12Eric Delabesse13Marlène Pasquet14Cyril Broccardo15Université de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleUniversité de Toulouse 3 Paul Sabatier, Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Equipe Labellisée Ligue Nationale Contre le Cancer 2023, Equipe labélisée Institut Carnot OpaleAbstract GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing molecular and functional approaches, we investigated the mutation’s impact on hematopoiesis, revealing significant alterations in the hematopoietic stem and progenitor (HSPC) compartment in young age. These include increased LT-HSC numbers, reduced self-renewal potential, and impaired response to acute inflammatory stimuli. The mature HSPC compartment was primarily affected at the CMP sub-population level. In the mutant LT-HSC population, we identified an aberrant subpopulation strongly expressing CD150, resembling aging, but occurring prematurely. This population showed hyporesponsiveness, accumulated over time, and exhibited allele-specific expression (ASE) favoring the mutated Gata2 allele, also observed in GATA2 mutated patients. Our findings reveal the detrimental impact of a Gata2 recurrent missense mutation on the HSC compartment contributing to its functional decline. Defects in the CMP mature compartment, along with the inflammatory molecular signature, explain the loss of heterogeneity in HPC compartment observed in patients. Finally, our study provides a valuable model that recapitulates the ASE-related pathology observed in GATA2 deficiency, shedding light on the mechanisms contributing to the disease’s natural progression.https://doi.org/10.1038/s41408-025-01213-z |
| spellingShingle | Laetitia Largeaud Vincent Fregona Laura A. Jamrog Camille Hamelle Stéphanie Dufrechou Naïs Prade Esmaa Sellam Pauline Enfedaque Manon Bayet Sylvie Hébrard Mathieu Bouttier Christine Didier Bastien Gerby Eric Delabesse Marlène Pasquet Cyril Broccardo GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome Blood Cancer Journal |
| title | GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome |
| title_full | GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome |
| title_fullStr | GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome |
| title_full_unstemmed | GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome |
| title_short | GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome |
| title_sort | gata2 mutated allele specific expression is associated with a hyporesponsive state of hsc in gata2 deficiency syndrome |
| url | https://doi.org/10.1038/s41408-025-01213-z |
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