Centre for Cancer research and Cell Biology (CCRCB)
School of Medicine, Dentistry and Biomedical Sciences
Gordon Piller PhD Studentship 2011
CCRCB
Criticality of the HoxA cluster in normal and malignant haematopoiesis
Supervisors: (email alex.thompson@qub.ac.uk) (email k.mills@qub.ac.uk)
Funding: Leukaemia Lymphoma Research. This prestigious four year award offers an
exceptionally attractive stipend of £17,000 per annum plus fees.
Candidates should have or expect to obtain a 2:1 or higher Honours degree or equivalent in Biomedical
Sciences, Biochemistry, Genetics, Bioinformatics or other relevant Biology degree.
Further information is available on the School website http://www.qub.ac.uk/schools/mdbs/ProspectiveStudents/pgd/PostgraduateResearch/PostgraduateStudentships/
Potential candidates are encouraged to contact the supervisor prior to submitting an application.
Aims:
The aim of this proposal is to establish (i) HOXA cluster conditional models of
leukaemia and (ii) Identify key HOX-TALE associated molecular pathways in AML.
Abstract:
HOX genes are highly expressed in normal haematopoietic stem (HSCs) and progenitor
cells but levels rapidly decrease during normal differentiation. In contrast elevated HOX
levels are maintained in leukaemia. A predominant role for the HOXA cluster in normal and
malignant haematopoiesis is supported. HOX expression is epigenetically regulated by
polycomb repressor complexes (PRCs) and histone modifiers e.g. Mixed Lineage
Leukaemia (MLL). Translocations involving HOX regulators, such as MLL, are frequent in
acute leukaemia however the role and necessity of the maintained HOX-TALE expression is
not fully elucidated. We recently reported impaired HSC function in a haploinsufficient HoxA
cluster model and have obtained conditionally null HoxA transgenic mice. We now propose
to generate MLL fusion driven leukaemias in the conditional background and determine the
criticality of HoxA in vivo by time-to-leukaemia assays. Significant loss or reduction in
leukaemia maintenance will be followed up by in vitro and in vivo rescue assays using
individual HoxA elements. In this way two important questions will be addressed: Are HoxA
cluster genes essential for leukaemia maintenance? Can overexpressed individual HoxA
genes account for the oncogenicity of the complete cluster? Completion of this project will
provide a basis for targeting key HOX interactions in leukaemia models
Plan of Investigation:
1.
2.
3.
Develop transplantable leukaemias conditional on HoxA expression using the
well-established Cre-Lox system.
Delete the HoxA cluster from these established leukaemia cells using retroviral
cre recombinase and examine their phenotype and leukaemic potential.
Identify key molecular pathways associated with HoxA dependency using micro
RNA and drug screening of these primary cells and associated human cell lines.
Our research group combines skills and experience in cell and molecular biology, stem cell
research, bone marrow transplantation, in vivo modelling and bioinformatics. The laboratory
is fully equipped to conduct advanced molecular biology analyses and stem cell research.
Key facilities include a Specific Pathogen Free research unit, gene expression profiling
platforms (Q-PCR and Affymetrix), Epigenetic assays (Pyrosequencing), Cell sorting and
dedicated Bioinformatics core.
The successful candidate will join a dynamic, multidisciplinary group, gaining comprehensive
theoretical and practical training in advanced technologies using state-of-the-art facilities.
Students are encouraged to attend external training courses providing in-depth knowledge
for key tasks and generic skills. The student will attend and contribute to weekly
Haematology Focus Group meetings and present their work at local, national and
international meetings. The CCRCB training programme will establish a strong foundation of
key skills that will allow the student to generate and submit high-quality research findings for
publication in peer-reviewed journals. This will enable them to subsequently obtain a
competitive post-doctoral research position.
This project will establish the criticality of the HoxA cluster in leukaemia and identify
key molecular pathways associated with the oncogenic potential of HoxA genes.
Targeting these key pathways may provide therapeutic benefit to leukaemia patients.
CLOSING DATE: Friday, 4 March 2011, at 5.00 pm
The application consists of two different processes:
(1) Candidates should apply via the Queen’s on-line portal:
https://dap.qub.ac.uk/portal/user/u_login.php
(2) a copy of your Curriculum Vitae including a synopsis of laboratory experience must
also be submitted to Dr Alex Thompson (alex.thompson@qub.ac.uk) by the relevant
closing date. Please ensure that you adhere to the closing dates above.
For more information, please consult our website www.qub.ac.uk/ccrcb.
Eligibility for both fees and maintenance depends on the applicant being either an ordinary UK
resident or those EU residents who have lived permanently in the UK for the 3 years immediately
preceding the start of the studentship. Non UK residents who hold EU residency may also apply
but if successful may receive fees only.