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3. A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.

Author

Li, Rong, Colombo, Michela, Wang, Guanlin, Rodriguez-Romera, Antonio, Benlabiod, Camelia, Jooss, Natalie J., O'Sullivan, Jennifer, Brierley, Charlotte K., Clark, Sally-Ann, Pérez Sáez, Juan M., Fernández, Pedro Aragón, Schoof, Erwin M., Porse, Bo, Meng, Yiran, Khan, Abdullah O., Wen, Sean, Dong, Pengwei, Zhou, Wenjiang, Sousos, Nikolaos, and Murphy, Lauren

Subjects
STEM cell niches, BONE marrow cells, MYELOPROLIFERATIVE neoplasms, MESENCHYMAL stem cells, SYMPTOM burden, MYELOFIBROSIS
Abstract

Myeloproliferative neoplasms are stem cell–driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside–binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell–niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis. Editor's summary: Myeloproliferative neoplasms can transition to advanced cancers with poor prognosis. Predicting progression and reversing the associated myelofibrosis remain difficult. Li, Colombo, and Wang et al. present a mouse cancer-stroma interactome for myelofibrosis and show that galectin-1 is a potential inflammation-related target for treating disease. Mesenchymal stem cells, eosinophils, basophils, and mast cells were each implicated in an inflammatory niche that drove myelofibrosis progression. Inhibiting galectin-1 with a monoclonal antibody in a mouse model of myeloproliferative neoplasm decreased fibrosis and cell proliferation and had a beneficial effect on survival. Galectin-1 was associated with myelofibrosis and poor survival in multiple human cohorts. These results suggest that galectin-1 may be a target to alter the inflammatory niche and to reduce fibrosis in myeloproliferative neoplasms. —Brandon Berry [ABSTRACT FROM AUTHOR]

Published
2024
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6. A pro-inflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis

Author

Li, Rong, primary, Colombo, Michela, additional, Wang, Guanlin, additional, Rodriguez-Romera, Antonio, additional, O'Sullivan, Jennifer, additional, Clark, Sally-Ann, additional, Pérez Sáez, Juan, additional, Meng, Yiran, additional, Khan, Abdullah, additional, Wen, Sean, additional, Dong, Pengwei, additional, Zhou, Wenjiang, additional, Sousos, Nikolaos, additional, Murphy, Lauren, additional, Clarke, Matthew, additional, Jooss, Natalie, additional, Olijnik, Aude-Anais, additional, Wong, Zoe, additional, Sirinukunwattana, Korsuk, additional, Ryou, Hosuk, additional, Norfo, Ruggiero, additional, Cheng, Qian, additional, Brierley, Charlotte, additional, Carrelha, Joana, additional, Ren, Zemin, additional, Thongjuea, Supat, additional, Rathinam, Vijay, additional, Krishnan, Anandi Krishnan, additional, Royston, Daniel, additional, Rabinovich, Gabriel, additional, Mead, Adam, additional, and Psaila, Bethan, additional

Published
2023
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8. Data from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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9. Supp Table 1 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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10. Supp Table 2 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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11. Supp Table 3 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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12. Supp Table 4 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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13. Supp Table 5 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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14. Supplementary Information from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, primary, Reyat, Jasmeet S., primary, Olijnik, Aude-Anais, primary, Colombo, Michela, primary, Wang, Guanlin, primary, Wen, Wei Xiong, primary, Sousos, Nikolaos, primary, Murphy, Lauren C., primary, Grygielska, Beata, primary, Perrella, Gina, primary, Mahony, Christopher B., primary, Ling, Rebecca E., primary, Elliott, Natalina E., primary, Karali, Christina Simoglou, primary, Stone, Andrew P., primary, Kemble, Samuel, primary, Cutler, Emily A., primary, Fielding, Adele K., primary, Croft, Adam P., primary, Bassett, David, primary, Poologasundarampillai, Gowsihan, primary, Roy, Anindita, primary, Gooding, Sarah, primary, Rayes, Julie, primary, Machlus, Kellie R., primary, and Psaila, Bethan, primary

Published
2023
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15. Supplementary Information from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Materials and Methods, Supplementary Figures S1-S12

Published
2023

16. Supp Table 3 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Table 3 HD and MPN samples.

Published
2023

17. Supp Table 1 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Table 1 VEGFAC Top Differentially Expressed Genes by Cluster

Published
2023

18. Supp Table 4 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

MM ALL Donor Details

Published
2023

19. Supp Table 2 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Table 2 Gene sets for GSEA

Published
2023

20. Supp Table 6 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Table 6 qRT PCR Probes

Published
2023

21. Supp Table 5 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Table 5 Antibodies

Published
2023

22. Supp Table 7 from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

Supplementary Table 7 NGS Panel

Published
2023

23. Data from Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Bethan Psaila, Kellie R. Machlus, Julie Rayes, Sarah Gooding, Anindita Roy, Gowsihan Poologasundarampillai, David Bassett, Adam P. Croft, Adele K. Fielding, Emily A. Cutler, Samuel Kemble, Andrew P. Stone, Christina Simoglou Karali, Natalina E. Elliott, Rebecca E. Ling, Christopher B. Mahony, Gina Perrella, Beata Grygielska, Lauren C. Murphy, Nikolaos Sousos, Wei Xiong Wen, Guanlin Wang, Michela Colombo, Aude-Anais Olijnik, Jasmeet S. Reyat, Antonio Rodriguez-Romera, and Abdullah O. Khan

Abstract

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow—stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers.Significance:We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.See related commentary by Derecka and Crispino, p. 263.This article is highlighted in the In This Issue feature, p. 247

Published
2023

24. Human Bone Marrow Organoids Enable the Study of Hematopoietic Cell-Stromal Interactions and Support the Survival of Malignant Cells from Patients

Author

Abdullah Khan, Antonio Rodriguez-Romera, Michela Colombo, Jasmeet S Reyat, Guanlin Wang, Wei Xiong Wen, Lauren C Murphy, Rebecca Ling, Natalina Elliott, Nikolaos Sousos, Samuel Kemble, Beata Grygielska, Christopher Mahoney, Andrew P. Stone, Adam P Croft, David Bassett, Gowsihan Poologasundarampillai, Adele K. Fielding, Emily A. Cutler, Anindita Roy, Sarah Gooding, Julie Rayes, Kellie Machlus, and Bethan Psaila

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

25. Cross-Talk between Hematopoietic Cells and Fibroblast Subsets Drives Inflammation and Remodelling of the Bone Marrow Microenvironment in Myeloproliferative Neoplasms

Author

Li, Rong, primary, Colombo, Michela, additional, Wang, Guanlin, additional, Clark, Sally-Ann, additional, Rodriguez-Romera, Antonio, additional, Meng, Yiran, additional, Khan, Abdullah, additional, Wen, Wei Xiong, additional, Sousos, Nikolaos, additional, Murphy, Lauren, additional, Simoglou Karali, Christina, additional, Sirinukunwattana, Korsuk, additional, O'Sullivan, Jennifer, additional, Norfo, Ruggiero, additional, Cheng, Qian, additional, Brierley, Charlotte, additional, Carrelha, Joana, additional, Ren, Zemin, additional, Rabinovich, Gabriel A., additional, Rathinam, Vijay A, additional, Thongjuea, Supat, additional, Royston, Daniel, additional, Mead, Adam J, additional, and Psaila, Bethan, additional

Published
2022
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26. Human Bone Marrow Organoids Enable the Study of Hematopoietic Cell-Stromal Interactions and Support the Survival of Malignant Cells from Patients

Author

Khan, Abdullah, primary, Rodriguez-Romera, Antonio, additional, Colombo, Michela, additional, Reyat, Jasmeet S, additional, Wang, Guanlin, additional, Wen, Wei Xiong, additional, Murphy, Lauren C, additional, Ling, Rebecca, additional, Elliott, Natalina, additional, Sousos, Nikolaos, additional, Kemble, Samuel, additional, Grygielska, Beata, additional, Mahoney, Christopher, additional, Stone, Andrew P., additional, Croft, Adam P, additional, Bassett, David, additional, Poologasundarampillai, Gowsihan, additional, Fielding, Adele K., additional, Cutler, Emily A., additional, Roy, Anindita, additional, Gooding, Sarah, additional, Rayes, Julie, additional, Machlus, Kellie, additional, and Psaila, Bethan, additional

Published
2022
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27. Developing a Flow Cytometric Signature of Carfilzomib Responsiveness in Myeloma

Author

Walker, Ieuan, primary, D'arcy, Venetia, additional, Rodriguez Romera, Antonio, additional, Anderson, Georgina, additional, Aubareda, Anna, additional, Roy, James, additional, Khandelwal, Garima, additional, Wilson, William, additional, Fitzsimons, Evelyn, additional, Galas-Filipowicz, Daria, additional, Foster, Kane, additional, Popat, Rakesh, additional, Ramasamy, Karthik, additional, Streetly, Matthew, additional, Bygrave, Ceri, additional, Benjamin, Reuben, additional, de Tute, Ruth M., additional, Camilleri, Marquita, additional, Chavda, Selina J, additional, Pang, Gavin, additional, Dadaga, Tushhar, additional, Kamora, Sumaiya, additional, Cavenagh, James, additional, Phillips, Elizabeth H., additional, Clifton-Hadley, Laura, additional, Owen, Roger G, additional, Herrero, Javier, additional, Yong, Kwee, additional, and Chapman, Michael A, additional

Published
2022
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28. Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Author

Khan, Abdullah O., primary, Rodriguez-Romera, Antonio, additional, Reyat, Jasmeet S., additional, Olijnik, Aude-Anais, additional, Colombo, Michela, additional, Wang, Guanlin, additional, Wen, Wei Xiong, additional, Sousos, Nikolaos, additional, Murphy, Lauren C., additional, Grygielska, Beata, additional, Perrella, Gina, additional, Mahony, Christopher B., additional, Ling, Rebecca E., additional, Elliott, Natalina E., additional, Karali, Christina Simoglou, additional, Stone, Andrew P., additional, Kemble, Samuel, additional, Cutler, Emily A., additional, Fielding, Adele K., additional, Croft, Adam P., additional, Bassett, David, additional, Poologasundarampillai, Gowsihan, additional, Roy, Anindita, additional, Gooding, Sarah, additional, Rayes, Julie, additional, Machlus, Kellie R., additional, and Psaila, Bethan, additional

Published
2022
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29. Podredumbre morena de los frutales de carozo Monilia fructicola, M. laxa

Author

Rodriguez Romera, Mariela Carmen

Subjects
Damage, Daños, Epidemiology, Fruit Crops, Fungal Diseases, Monilinia fructicola, Monilinia, Frutales, Epidemiologia, Enfermedades Fungosas
Abstract

A nivel mundial, la podredumbre morena es la enfermedad ocasionada por hongos más importante en los frutales de carozo (especies del género Prunus). Su importancia radica en que ataca flores, brotes y frutos, originando la destrucción de los mismos, y además por ser una enfermedad de difícil control. En el mundo existen tres especies dentro del género Monilinia que pueden producir la enfermedad: Monilinia fructicola (G: Winter) Honey, anamorfo Monilia fruticola Batra; Monilinia laxa (Adert. y Ruhland) Honey, anamorfo Monilia laxa (Ehrenb.) Sacc. y Voglino; Monilinia frutigena Honey ex Whetzel, anamorfo Monilia fructigena Persoon:Fr. En Argentina sólo se encuentran presentes las especies de M. fructicola y M. laxa. Se trata de un hongo superior perteneciente a la subdivisión Ascomycotina. Produce dos tipos de esporas: ascoporas de origen sexual contenidas en asca, las que se forman en cuerpos fructíferos denominados apotecios, y conidios de origen asexual, dispuestos en cadenas. EEA Mendoza Fil: Rodriguez Romera, Mariela Carmen. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mendoza; Argentina

Published
2022

30. Podredumbre ácida de los racimos Levaduras y bacterias acéticas

Author

Rodriguez Romera, Mariela Carmen

Subjects
Issatchenkia orientalis, Gluconobacter, Epidemiology, Vid, Levadura, Pichia, Podredumbres, Grapevines, Saccharomyces, Damage, Daños, Yeasts, Bacteria Acetica, Acetobacter, Acetic Acid Bacteria, Epidemiologia, Rots
Abstract

La enfermedad es causada por levaduras (Saccharomyces cerevisiae, Issatchenkia orientalis, Pichia membranifaciens y P. galeiformes) y bacterias acéticas (Acetobacter y Gluconobacter). En Argentina, la podredumbre ácida se presenta desde el año 2001 y desde entonces ha ido aumentando su intensidad y severidad. En las zonas vitícolas de Francia fue detectada hace más de un siglo, mientras que en nuestra zona su presencia antes del tiempo citado se desconoce, ya que esta enfermedad frecuentemente se la confundía con la “podredumbre de los racimos”, producida por un complejo parasitario donde intervienen principalmente hongos. La presencia de fisuras o microheridas en el hollejo es el factor desencadenante de la enfermedad. Estas permiten la entrada de levaduras y bacterias de la microflora del viñedo. Las levaduras producen alcohol por la degradación de los azúcares de las bayas. Las bacterias oxidan el alcohol a ácido acético. La pérdida de mosto permite el desarrollo de hongos filamentosos como patógenos secundarios. EEA Mendoza Fil: Rodriguez Romera, Mariela Carmen. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mendoza; Argentina

Published
2022

31. S246: A HUMAN BONE MARROW ORGANOID FOR DISEASE MODELLING AND DRUG SCREENING IN BLOOD CANCERS

Author

Khan, A., primary, Colombo, M., additional, Reyat, J., additional, Wang, G., additional, Rodriguez-Romera, A., additional, Wen, W. X., additional, Murphy, L., additional, Grygielska, B., additional, Mahoney, C., additional, Stone, A., additional, Croft, A., additional, Bassett, D., additional, Poologasundarampillai, G., additional, Roy, A., additional, Gooding, S., additional, Rayes, J., additional, Machlus, K., additional, and Psaila, B., additional

Published
2022
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32. Cross-Talk between Hematopoietic Cells and Fibroblast Subsets Drives Inflammation and Remodelling of the Bone Marrow Microenvironment in Myeloproliferative Neoplasms

Author

Rong Li, Michela Colombo, Guanlin Wang, Sally-Ann Clark, Antonio Rodriguez-Romera, Yiran Meng, Abdullah Khan, Wei Xiong Wen, Nikolaos Sousos, Lauren Murphy, Christina Simoglou Karali, Korsuk Sirinukunwattana, Jennifer O'Sullivan, Ruggiero Norfo, Qian Cheng, Charlotte Brierley, Joana Carrelha, Zemin Ren, Gabriel A. Rabinovich, Vijay A Rathinam, Supat Thongjuea, Daniel Royston, Adam J Mead, and Bethan Psaila

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

33. Developing a Flow Cytometric Signature of Carfilzomib Responsiveness in Myeloma

Author

Ieuan Walker, Venetia D'arcy, Antonio Rodriguez Romera, Georgina Anderson, Anna Aubareda, James Roy, Garima Khandelwal, William Wilson, Evelyn Fitzsimons, Daria Galas-Filipowicz, Kane Foster, Rakesh Popat, Karthik Ramasamy, Matthew Streetly, Ceri Bygrave, Reuben Benjamin, Ruth M. de Tute, Marquita Camilleri, Selina J Chavda, Gavin Pang, Tushhar Dadaga, Sumaiya Kamora, James Cavenagh, Elizabeth H. Phillips, Laura Clifton-Hadley, Roger G Owen, Javier Herrero, Kwee Yong, and Michael A Chapman

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

34. Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

Author

Abdullah O. Khan, Michela Colombo, Jasmeet S. Reyat, Guanlin Wang, Antonio Rodriguez-Romera, Wei Xiong Wen, Lauren Murphy, Beata Grygielska, Chris Mahoney, Andrew Stone, Adam Croft, David Bassett, Gowsihan Poologasundarampillai, Anindita Roy, Sarah Gooding, Julie Rayes, Kellie R Machlus, and Bethan Psaila

Abstract

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow - stroma, lumen-forming sinusoidal vessels and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.Significance StatementWe present a 3D, vascularised human bone marrow organoid that supports growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment, and provides a much-needed, ex vivo tool for prioritization of new therapeutics.

Published
2022

36. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Author

Suthesh Sivapalaratnam, Erica De Candia, Janine Collins, Anthony D. Whetton, Nihr BioResource, Rachel Reed, Wadie F. Bahou, Denis Seyres, Daniel Greene, Hanna Shalev, Anne M. Kelly, Sandra Le Quellec, Paolo Gresele, Thierry M Leblanc, Elizabeth Chalmers, Tadbir K. Bariana, Rémi Favier, John Pasi, Albert Sickmann, Kathleen Freson, Sri V V Deevi, Daniel P. Hart, Dave Lee, Ernest Turro, Rutendo Mapeta, Luigi Grassi, John K. Wu, Matthew C Sims, Sara Morais, Mattia Frontini, Barbara Zieger, Diane J. Nugent, Mallika Sekhar, Louisa Mayer, Loredana Bury, Man-Chiu Poon, Soo J. Park, William J. Astle, Frances Burden, Paquita Nurden, Jonathan Stephens, Cécile Lavenu-Bombled, Andreas Greinacher, Rachael Da Silva, Marie-Françoise Hurtaud, Jose A. Guerrero, Robert Campbell Tait, Sofia Papadia, Eva Leinoe, Antonio Rodriguez-Romera, Karyn Megy, Wendy N. Erber, Gian Marco Podda, Ron Kerr, Willem H. Ouwehand, Laxmikanth Kollipara, Marie-Christine Alessi, Keith Gomez, Harriet McKinney, Taco W. Kuijpers, Alan D. Michelson, Kate Downes, Samantha Farrow, and Orna Steinberg-Shemer

Subjects
Autoimmune disease, 0303 health sciences, business.industry, Autoantibody, Inflammation, Immune dysregulation, medicine.disease_cause, medicine.disease, 3. Good health, Gray platelet syndrome, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine.anatomical_structure, Megakaryocyte, Immunology, medicine, Bone marrow, medicine.symptom, business, 030304 developmental biology, 030215 immunology
Abstract

Gray platelet syndrome (GPS) is a rare recessive disorder caused by variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet ɑ-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macro-thrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4-lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.

Published
2020

37. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Author

Tadbir K. Bariana, William J. Astle, Paquita Nurden, Jonathan Stephens, Sandra Le Quellec, Suthesh Sivapalaratnam, Andreas Greinacher, Jose A. Guerrero, Karyn Megy, Laxmikanth Kollipara, Hanna Shalev, Rachel Reed, Marie-Christine Alessi, Ron Kerr, Anthony D. Whetton, Matthew C Sims, Nihr BioResource, Man-Chiu Poon, Kathleen Freson, Samantha Farrow, Orna Steinberg-Shemer, Wendy N. Erber, Diane J. Nugent, Harriet McKinney, Cécile Lavenu-Bombled, Robert Campbell Tait, Mallika Sekhar, Rutendo Mapeta, Eva Leinoe, Anne M. Kelly, Louisa Mayer, Janine Collins, Mattia Frontini, Thierry M Leblanc, Elizabeth Chalmers, Albert Sickmann, Willem H. Ouwehand, Barbara Zieger, Taco W. Kuijpers, Antonio Rodriguez-Romera, Gian Marco Podda, Daniel P. Hart, Paolo Gresele, Daniel Greene, Keith Gomez, Wadie F. Bahou, Soo J. Park, Erica De Candia, Dave Lee, Luigi Grassi, Alan D. Michelson, Sara Morais, Denis Seyres, Kate Downes, John Pasi, Sri V V Deevi, John K. Wu, Loredana Bury, Frances Burden, Rachael Da Silva, Sofia Papadia, Marie-Françoise Hurtaud, Ernest Turro, Rémi Favier, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Cambridge [UK] (CAM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Manchester [Manchester], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of Perugia, Royal Hospital for Sick Children [Edinburgh], Catholic University School of Medicine, Royal Free London NHS Foundation Trust, Universitätsmedizin Greifswald, Queen Mary University of London (QMUL), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Ninewells Hospital and Medical School [Dundee], Hospices Civils de Lyon (HCL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Harvard Medical School [Boston] (HMS), Centro Hospitalar Universitário do Porto, Children's Hospital of Orange County, University of California, Università degli Studi di Milano [Milano] (UNIMI), University of Calgary, Manchester Academic Health Science Centre (MAHSC), Ben-Gurion University of the Negev (BGU), Tel Aviv University [Tel Aviv], Glasgow Royal Infirmary, University of British Columbia (UBC), University of Freiburg [Freiburg], VU University Medical Center [Amsterdam], University of Aberdeen, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The University of Western Australia (UWA), Hôpital Xavier Arnozan, Università degli Studi di Perugia = University of Perugia (UNIPG), University of California (UC), Università degli Studi di Milano = University of Milan (UNIMI), Tel Aviv University (TAU), and Prémilleux, Annick

Subjects
Biopsy, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, medicine.disease_cause, GUIDELINES, NBEAL2, Biochemistry, Cohort Studies, 0302 clinical medicine, Megakaryocyte, Gene Frequency, Medicine, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ABNORMALITIES, Hematology, Blood Proteins, ASSOCIATION, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Phenotype, BEACH-DOMAIN, Immune System Diseases, medicine.symptom, BLOOD Commentary, Platelet disease, NEUROBEACHIN-LIKE 2, PROTEINS, Immunology, education, Inflammation, Cytoplasmic Granules, Gray Platelet Syndrome, CLASSIFICATION, Gray platelet syndrome, Diagnosis, Differential, 03 medical and health sciences, Genetic Heterogeneity, Immune system, Humans, Genetic Association Studies, 030304 developmental biology, Autoimmune disease, business.industry, Autoantibody, Grey platelet syndrome, Cell Biology, Immune dysregulation, medicine.disease, Bleeding disease, PROTEOME, Settore MED/15 - MALATTIE DEL SANGUE, Case-Control Studies, Immune System, Mutation, Bone marrow, business, PATHOGENICITY, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease. ispartof: BLOOD vol:136 issue:17 pages:1956-1967 ispartof: location:United States status: published

Published
2020

38. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Author

Sims, Matthew C, Mayer, Louisa, Collins, Janine, Bariana, Tadbir, Megy, Karyn, Lavenu-Bombled, Cecile, Seyres, Deni, Kollipara, Laxmikanth, Burden, France, Greene, Daniel, Lee, Dave, Rodriguez-Romera, Antonio, Alessi, Marie-Christine, Astle, William John, Bahou, Wadie, Bury, Loredana, Chalmers, Elizabeth, Da Silva, Rachael, De Candia, Erica, Deevi, Sri V V, Farrow, Samantha, Gomez, Keith, Grassi, Luigi, Greinacher, Andrea, Gresele, Paolo, Hart, Daniel Patrick, Hurtaud, Marie-Françoise, Kelly, Anne, Kerr, Ron, Le Quellec, Sandra, Leblanc, Thierry M, Leinøe, Eva B, Mapeta, Rutendo P, Mckinney, Harriet, Michelson, Alan D, Morais, Sara, Nugent, Diane J, Papadia, Sofia, Park, Soo J, Pasi, John, Podda, Gian Marco, Poon, Man-Chiu, Reed, Rachel, Sekhar, Mallika, Shalev, Hanna, Sivapalaratnam, Suthesh, Steinberg-Shemer, Orna, Stephens, Jonathan C, Tait, Robert C, Turro, Ernest, Wu, John K, Zieger, Barbara Maria Hildegard, Bioresource, Nihr, Kuijpers, Taco W, Whetton, Anthony D, Sickmann, Albert, Freson, Kathleen, Downes, Kate, Erber, Wendy, Frontini, Mattia, Nurden, Paquita, Ouwehand, Willem Hendrik, Favier, Remi, Guerrero, Jose A, De Candia, Erica (ORCID:0000-0003-0942-2819), Sims, Matthew C, Mayer, Louisa, Collins, Janine, Bariana, Tadbir, Megy, Karyn, Lavenu-Bombled, Cecile, Seyres, Deni, Kollipara, Laxmikanth, Burden, France, Greene, Daniel, Lee, Dave, Rodriguez-Romera, Antonio, Alessi, Marie-Christine, Astle, William John, Bahou, Wadie, Bury, Loredana, Chalmers, Elizabeth, Da Silva, Rachael, De Candia, Erica, Deevi, Sri V V, Farrow, Samantha, Gomez, Keith, Grassi, Luigi, Greinacher, Andrea, Gresele, Paolo, Hart, Daniel Patrick, Hurtaud, Marie-Françoise, Kelly, Anne, Kerr, Ron, Le Quellec, Sandra, Leblanc, Thierry M, Leinøe, Eva B, Mapeta, Rutendo P, Mckinney, Harriet, Michelson, Alan D, Morais, Sara, Nugent, Diane J, Papadia, Sofia, Park, Soo J, Pasi, John, Podda, Gian Marco, Poon, Man-Chiu, Reed, Rachel, Sekhar, Mallika, Shalev, Hanna, Sivapalaratnam, Suthesh, Steinberg-Shemer, Orna, Stephens, Jonathan C, Tait, Robert C, Turro, Ernest, Wu, John K, Zieger, Barbara Maria Hildegard, Bioresource, Nihr, Kuijpers, Taco W, Whetton, Anthony D, Sickmann, Albert, Freson, Kathleen, Downes, Kate, Erber, Wendy, Frontini, Mattia, Nurden, Paquita, Ouwehand, Willem Hendrik, Favier, Remi, Guerrero, Jose A, and De Candia, Erica (ORCID:0000-0003-0942-2819)

Abstract

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet ɑ-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 32 new etiological variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4-lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.

Published
2020

39. Novel yeast isolated from broilers’ feedstuff, gut and faeces as aflatoxin B1adsorbents

Author

Sebastián Chiacchiera, Ana Maria Dalcero, Alejandra Paola Magnoli, Lilia Reneé Cavaglieri, Mariela Carmen Rodriguez Romera, Mariana Combina, Valeria Poloni, and María Cecilia Rojo

Subjects
0301 basic medicine, 03 medical and health sciences, Aflatoxin, 030104 developmental biology, Chemistry, 030106 microbiology, General Medicine, Food science, Applied Microbiology and Biotechnology, Feces, Yeast, Biotechnology
Published
2016

41. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Author

Sims, Matthew C., Mayer, Louisa, Collins, Janine H., Bariana, Tadbir K., Megy, Karyn, Lavenu-Bombled, Cecile, Seyres, Denis, Kollipara, Laxmikanth, Burden, Frances S., Greene, Daniel, Lee, Dave, Rodriguez-Romera, Antonio, Alessi, Marie-Christine, Astle, William J., Bahou, Wadie F., Bury, Loredana, Chalmers, Elizabeth, Da Silva, Rachael, De Candia, Erica, Deevi, Sri V. V., Farrow, Samantha, Gomez, Keith, Grassi, Luigi, Greinacher, Andreas, Gresele, Paolo, Hart, Dan, Hurtaud, Marie-Françoise, Kelly, Anne M., Kerr, Ron, Le Quellec, Sandra, Leblanc, Thierry, Leinøe, Eva B., Mapeta, Rutendo, McKinney, Harriet, Michelson, Alan D., Morais, Sara, Nugent, Diane, Papadia, Sofia, Park, Soo J., Pasi, John, Podda, Gian Marco, Poon, Man-Chiu, Reed, Rachel, Sekhar, Mallika, Shalev, Hanna, Sivapalaratnam, Suthesh, Steinberg-Shemer, Orna, Stephens, Jonathan C., Tait, Robert C., Turro, Ernest, Wu, John K. M., Zieger, Barbara, Kuijpers, Taco W., Whetton, Anthony D., Sickmann, Albert, Freson, Kathleen, Downes, Kate, Erber, Wendy N., Frontini, Mattia, Nurden, Paquita, Ouwehand, Willem H., Favier, Remi, and Guerrero, Jose A.

Abstract

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.

Published
2020
Full Text
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42. Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.

Author

Khan AO, Rodriguez-Romera A, Reyat JS, Olijnik AA, Colombo M, Wang G, Wen WX, Sousos N, Murphy LC, Grygielska B, Perrella G, Mahony CB, Ling RE, Elliott NE, Karali CS, Stone AP, Kemble S, Cutler EA, Fielding AK, Croft AP, Bassett D, Poologasundarampillai G, Roy A, Gooding S, Rayes J, Machlus KR, and Psaila B

Subjects
Humans, Bone Marrow Cells physiology, Bone Marrow Transplantation, Organoids, Tumor Microenvironment, Bone Marrow, Hematologic Neoplasms
Abstract

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow-stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers., Significance: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics. See related commentary by Derecka and Crispino, p. 263. This article is highlighted in the In This Issue feature, p. 247., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2023
Full Text
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