CRUK Career Development Fellow

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Research themes:

Developmental Haematopoiesis

Description of research

The number and characteristics of each type of blood cells are frequently used in clinical practice and deviations outside the normal ranges can be indicative of a wide array of blood pathologies. It is becoming increasingly clear that genetic changes acquired throughout life play an important role in initiation of blood disorders including blood cancers.

In the last few years, DNA sequencing technologies have been developed that allow the identification of every genetic change in a given cancer sample, promising a new harvest of cancer genes. However, many of the identified genes were not previously implicated in blood formation and there is a real need to investigate the biology and potential therapeutic aspects of these genes. The aim of the group is to bridge this knowledge gap by providing a method in a relevant model organism (zebrafish, Danio rerio) that will allow the dissection of the role of the cancer genes with a hitherto unknown function and to determine their hierarchical position in the regulatory networks that underlie haematopoiesis. This will be achieved by pursuing two main objectives:

First, a high-throughput screen in zebrafish to dissect the functional role of novel cancer genes, implicated in myelodysplasia and myeloproliferative neoplasms, in haematopoiesis. This effort will define the function of novel cancer genes in blood cell formation by a morpholino knock-down approach in zebrafish.

This early objective will be followed by a far more ambitious long-term one. This objective will be based on in-depth functional characterisation of a subset of genes that encode proteins involved in RNA splicing and it will delineate the effect of acquired coding sequence variants on their function.

If successful, this research will be the major first step towards systematic, high-throughput functional characterisation of newly identified genes implicated in haematopoietic malignancies in a relevant in vivo model system and will explore the realms of acquired and function-modifying genetic variants.

Research focus

Keywords: Haematopoiesis Zebrafish Functional Genomics Myelodysplastic Syndrome

Clinical conditions: Myelodysplastic Syndrome Haematopoietic Malignancies

Methodologies: Microinjections; In situ hybridisation; Morpholino knock-down; Live imaging; Zebra fish model in functional genomics

Key Publications

Bielczyk-Maczyńska E, Serbanovic-Canic J, Ferreira L, Soranzo N, Stemple D, Ouwehand WH, Cvejic A (2014). A loss of function screen of identified genome-wide association study loci reveals new genes controlling haematopoiesis. PLOS Genetics, in press.

Cvejic A*,, Haer-Wigman L*, Stephens JC*, Kostadima M, Smethurst PA, Frontini M, Sipos B, Akker Evd, Bertone P, Bielczyk E, Farrow S, Fehrmann RSN, Gray A, Haas M, Haver VG, Jordan G, Karjalainen J, Kerstens HHD, Kiddle G, Loyd-Jones H, Needs M, Poole J, Soussan A, Rendon A, Rieneck K, Sambrook JG, Schepers H, Siljer HHW, Swinkels D, Tamuri AU, Verweij N, Watkins NA, Westra HJ, Stemple D, Franke L, Soranzo N, Stunnenberg HG, Goldman N, Harst Pvd, C Schoot Evd, Ouwehand WH, Albers C (2013). The red blood cell GWAS gene SMIM1 underlies the Vel blood group and is a novel regulator of red blood cell formation. Nature Genetics, 45(5):542-5.

Gieger C*, Radhakrishnan A*, Cvejic A*, Tang W*, Porcu E*, Pistis G*, Serbanovic-Canic J*, [150 other contributing authors], Sanna S, Hicks AA, Rendon A, Ferreira MA, Ouwehand WH, Soranzo N (2011). New gene functions in megakaryopoiesis and platelet formation. Nature, 480(7376): 201-8.

Serbanovic-Canic J*, Cvejic A*, Soranzo N, Stemple DL, Ouwehand WH, Freson K (2011). Silencing of RhoA nucleotide exchange factor, ARHGEF3 reveals its unexpected role in iron uptake. Blood, 118(18): 4967-76.

Albers CA*, Cvejic A*, Favier R, Bouwmans E, Alessi MC, Jordan G, Kiddle G, Kostadima, R Read, Sipos B, Smethurst P, Stephens J, Voss K, Nurden A, Rendon AM, Nurden P and Ouwehand WH (2011). Exome sequencing identifies NBEAL2 as the causative gene for Gray Platelet Syndrome. Nature Genetics, 43(8): 735-7.

(*joint first authors, corresponding authors)