Mechanistic role of CUX1 in haematopoiesis and leukaemogenesis and identification of therapeutic vulnerabilities in CUX1-deficient malignancies. (360G-Wellcome-105914_Z_14_Z)

£704,856

Complete or partial monoallelic losses of chromosome 7 [-7/del(7q)] are recurrent lesions observed in myelodysplasia (MDS) and acute myeloid leukaemia (AML), suggesting that chromosome 7q harbours tumour suppressors that promote disease development. Although these gene targets have been elusive, we recently identified inactivating mutations in the chromosome 7q transcription factor gene, CUX1, in MDS and AML cases, thereby implicating CUX1 as a key target gene lost in -7/del(7q) MDS and AML. In support, CUX1 mutations were found to confer adverse survival similar to the poor prognosis of -7/del(7q) MDS and AML cases. This proposal firstly aims to elucidate the function of CUX1 in haematopoiesis and leukaemogenesis in vivo by using a novel conditional Cux1 knockout mouse model we have generated. Secondly, by using genome-editing and transposon-mediated expression systems to generate epitope-tagged cell lines, this proposal aims to identify CUX1 target genes and interacting proteins that are critical mediators of CUX1 function. Finally, CUX1-deficient cells will be subjected to large-scale drug-sensitivity and genome-wide genetic synthetic lethality screens to identify drugs and genetic pathways that specifically target CUX1-deficient tumours. These complementary approaches will enhance our understanding of the role of CUX1 in cancer and identify potential new treatments for these poor-prognosis disorders.

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Grant Details

Amount Awarded 704856
Applicant Surname Wong
Approval Committee Clinical Interview Committee
Award Date 2014-11-13T00:00:00+00:00
Financial Year 2014/15
Grant Programme: Title Intermediate Clinical Fellowship
Internal ID 105914/Z/14/Z
Lead Applicant Dr Chi Wong
Partnership Value 704856
Planned Dates: End Date 2020-02-01T00:00:00+00:00
Planned Dates: Start Date 2015-01-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
Sponsor(s) Dr David Adams