Zebrafish Models of Haematopoietic Disease
Group Leader: Dr Elspeth (Beth) Payne
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, as shown for Rps14 in Figure 1.
Figure 1. Four day old zebrafish stained for haemoglobin (head left, tail right). The upper panel shows normal blood in a control fish (inset shows the heart and major blood vessels in the head region). The lower panel shows a fish with only 50% normal levels of ribosomal protein s14 (Rps14), which lacks detectable haemoglobin. Loss of Rps14 is implicated in the pathogenesis of the anaemia in patients with some forms of myelodysplastic syndrome. Image detail
Our current research focuses of 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.
Determining Novel therapeutics for Ribosomal protein deficiency using zebrafish small molelcule screening
Figure 2. Schematic of high content screening of ribosomal protein deficient zebrafish embryos, for amelioration of anaemia following exposure to small molecules. Embryos are arrayed in 96 well plates and after 24 hours exposed to a library of small molecules. At 4 days after fertilisation embryos are assayed using red fluorescent reporter expressed in erythroid cells for any alleviation in anaemia.
Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F, Payne E, Mansour M, Dahlberg SE, Neuberg DS, den Hertog J, Prochownik EV, Testa JR, Harris M, Kanki JP, Look AT. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med. 2011 Aug 1;208(8):1595-603. PMID: 21727187. Pubmed
*Elspeth M Payne, Niccolo Bolli, Jennifer Rhodes, Omar Abdel-Wahab, Ross L Levine, Cyrus Hedvat, Richard Stone, Arati Khanna-Gupta, Hong Sun, John Kanki, Hanna T Gazda, Alan H Beggs, Finbarr Cotter, and A. Thomas Look Ddx18 is essential for cell cycle progression in zebrafish hematopoietic cells and is mutated in human acute myeloid leukemia Blood 2011; Jul 28;118(4):903-15 PMID: 21653321 *corresponding author. Pubmed
Niccolò Bolli, Elspeth M. Payne, Jennifer Rhodes, Adam B. Johnston, Clemens Grabher, Jeong-Soo Lee, John P. Kanki and A. Thomas Look Cpsf1 is required for definitive hematopoietic stem cell survival in zebrafish Blood April 2011 PMID: 21330472. Pubmed
Clemens Grabher*, Elspeth M. Payne*, Adam B. Johnston, Niccolo Bolli, Eric Lechman, John E. Dick, John P. Kanki, A. Thomas Look Zebrafish miR-126 and miR-150 coordinately control hematopoietic cell fate by regulating the c-Myb proto-oncogene Leukemia Nov 2010 *equal contribution PMID: 21079614. Pubmed
Niccolò Bolli*, Elspeth M. Payne*, Clemens Grabher, Jeong-Soo Lee, Adam B. Johnston, Brunangelo Falini, John P. Kanki and A. Thomas Look Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of primitive myeloid cells and definitive hematopoietic stem cells in zebrafish Blood 2010 Apr 22;115(16):3329-40.*equal contribution PMID: 20197555. Pubmed
- Dr Elspeth (Beth) Payne
- Maria Virgilio
- Jurg Bahler (UCL)
- Clemens Grabher (Karlsruhe Institute of Technology)
- Tariq Enver (UCL)
- Hannah Gazda (Childrens Hospital Boston)