Zebrafish Models of Haematopoietic Disease

The development of blood initiates during early embryogenesis. This process is highly conserved in vertebrates, from fish to humans. Genes that are mutated in hematopoietic malignancies and disease are often required for the normal maintenance and production of blood cells not only in adult tissues but in the developing embryo. Therefore defining the genetic events and interactions governing blood development can provide important insights into the pathogenesis of haematopoietic malignancies. With these facts in mind our laboratory utilize the zebrafish, a small freshwater fish to model human blood disorders to allow us to gain insight into their genetic basis and to develop novel therapies.

We use zebrafish with knockdown of the ribosomal protein genes Rps19, Rps26 and Rpl11 in during development to model the congenital red cell aplasia, Diamond-Blackfan Anaemia (DBA). In parallel we have developed a zebrafish with loss of Rps14 which is thought to be the major genetic determinant in the anaemia observed in patients with a subtype of myelodysplastic syndrome, the 5q minus syndrome. Like the human diseases arising from loss of ribosomal proteins, zebrafish with loss of these ribosomal proteins show evidence of a profound anaemia.

Our current research focuses on the following areas:

1. Assessing the role of aberrant translation in ribosomal protein mediated human blood diseases such as DBA and 5q- MDS.
2. Identifying novel therapeutics for DBA and 5q- MDS using high content screening of zebrafish embryos as shown in Figure 2.
3. Translating findings into primary human cells to validate novel therapeutics for future studies.

Selected references

1. Lubin A, Hockings C, Hoade Y ... Payne E. Identifying PTPRJ As a Novel Mediator of CEBPA-Mutated AML. Blood. 2023 Nov 28; 142 (Supplement 1): 2755.
2. Nuttall Musson E, Miller RE, Mansour MR ... Payne EM. Monitoring clone dynamics and reversibility in clonal haematopoiesis and myelodysplastic neoplasm associated with PARP inhibitor therapy-a role for early monitoring and intervention. Leukemia. 2024 Jan;38(1): 215-218.
3. Ferrada MA, Savic S, Cardona DO ... Payne EM, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood. 2022 Sep 29;140(13): 1496-1506.
4. Chan WY, Zhu C, Sanchez E ... Payne EM, O'Nions J. Antibody responses to SARS-CoV-2 vaccination in patients with acute myeloid leukaemia and high risk MDS on active anti-cancer therapies. Br J Haematol. 2022 Aug;198(3): 478-481.
5. Otterstrom JJ, Lubin A, Payne EM, Paran Y. Technologies bringing young Zebrafish from a niche field to the limelight. SLAS Technol. 2022 Apr;27(2): 109-120.
6. Avenoso D, Marsh JCW, Potter V ... Payne E, Gandhi S, Kulasekararaj AG. SARS-CoV-2 infection in aplastic anemia. Haematologica. 2022 Feb 1;107(2): 541-543.
7. Peña OA, Lubin A, Hockings C ... Payne EM. TLR7 ligation augments hematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signaling. Blood Adv. 2021 Oct 26;5(20): 4112-4124.
8. Lubin A, Otterstrom J, Hoade Y ... Payne E. A versatile, automated and high-throughput drug screening platform for zebrafish embryos. Biol Open. 2021 Sep 15;10(9): bio058513.
9. Peña OA, Lubin A, Rowell J ... Payne EM. Differential Requirement of Gata2a and Gata2b for Primitive and Definitive Myeloid Development in Zebrafish. Front Cell Dev Biol. 2021 Sep 13;9: 708113.
10. Killick SB, Ingram W, Culligan D, Enright H, Kell J, Payne EM, et al. British Society for Haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol. 2021 Jul;194(2): 267-281.
11. Killick SB, Wiseman DH, Quek L ... Payne EM, et al. British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes. Br J Haematol. 2021 Jul;194(2): 282-293.
12. Simini G, Mackenzie S, Gohil S, Papanikolaou X, Manson J, Payne E. Successful use of allogeneic bone marrow transplantation in a patient with myelodysplastic syndrome presenting with autoimmune manifestations. Br J Haematol. 2021 Jun;193(6): 1275-1277.

Group members

• Dr Elspeth (Beth) Payne
• Maria Virgilio

Collaborators

• Jurg Bahler (UCL)
• Clemens Grabher (Karlsruhe Institute of Technology)
• Tariq Enver (UCL)
• Hannah Gazda (Children's Hospital Boston)

Funders