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Haematology: Oncogenic mechanisms causing malignant transformation of lymphoid cells

PGR-P-396

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Professor Ulf Klein
<h2 class="heading hide-accessible">Summary</h2>

Cancers of B cells and plasma cells, lymphomas and multiple myeloma, can be very aggressive, and often the cancer rapidly reoccurs after standard therapy. In the UK alone, approximately 14,000 lymphoma and 6,000 myeloma cases are diagnosed each year, with 5,000 and 3,000 deaths, respectively. Thus, there is a clinical need for more effective therapies against these malignancies, which requires a better understanding of the biology of these cancers. <br /> <br />

<h2 class="heading hide-accessible">Full description</h2>

<p>Towards this goal, identifying the molecular processes underlying the malignant transformation of B cells and plasma cells is critical for understanding the development of lymphomas and multiple myeloma. This knowledge will provide the rationale and molecular basis for personalized medicine in the treatment of these aggressive malignancies. &nbsp;&nbsp;<br /> &nbsp;<br /> A major player in the pathogenesis of aggressive lymphomas and myeloma is aberrant signaling through the nuclear factor-&kappa;B (NF-&kappa;B) transcription factor complex due to genetic mutations. These observations identify targeting of aberrant NF-&kappa;B signaling as a treatment strategy. However, the NF-&kappa;B-signaling cascade is extremely complex, consisting of two separate pathways and several distinct transcription factors. Unravelling the complexity of NF-&kappa;B signaling in the tumour cells is crucial in order to identify the precise, therapeutically targetable molecular components of this pathway. This is particularly important because global inhibition of the entire NF-&kappa;B signaling pathway results in systemic toxicity.</p> <p>Since NF-&kappa;B activation ultimately leads to the nuclear translocation of five different NF-&kappa;B transcription factor subunits that transcribe target genes, a conceivable strategy for inhibiting aberrant NF-&kappa;B activation in a more selective, less toxic way would be to target the downstream transcription factors that are oncogenic in the cancer, or their target genes. We have published and preliminary data demonstrating that particular normal B cells and certain lymphoid malignancies can indeed depend for their growth and survival on the activity of distinct NF-&kappa;B subunits rather than on the activation of all NF-&kappa;B subunits. &nbsp; &nbsp;&nbsp;</p> <p>This project is aimed at&nbsp;identifying&nbsp;the role of the distinct&nbsp;NF-&kappa;B&nbsp;transcription factors in subtypes of&nbsp;lymphomas and myeloma.&nbsp;The separate&nbsp;NF-&kappa;B&nbsp;subunits will be functionally ablated by gene silencing and CRISPR-knockout in cell lines using retrovirus-mediated approaches, which will identify their requirement for&nbsp;tumour-cell growth and&nbsp;survival. Transcriptional targets of the subunits will be identified by integrating RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses through bioinformatics approaches.&nbsp;Identified targets will be validated and tracked in patient biopsies.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</p> <p>Techniques associated with project</p> <p>In addition to the techniques mentioned above,&nbsp;validation of the identified targets will involve a broad range of molecular and cell biology techniques, including cloning, PCR, gel electrophoresis, Western blotting, ELISA, flow cytometry, immunohistochemistry, and metabolic flux analyses.&nbsp;</p> <p>References</p> <ol role="list" start="1"> <li aria-setsize="-1" data-aria-level="1" data-aria-posinset="1" data-font="Arial" data-leveltext="%1)" data-listid="20" role="listitem"> <p paraeid="{1643af60-c312-489d-8381-caa3af30baa0}{199}" paraid="451270182">Kennedy, R. &amp;&nbsp;U. Klein. (2018) Aberrant activation of NF-&kappa;B signaling in aggressive lymphoid malignancies.&nbsp;Cells&nbsp;7(11):189.&nbsp;</p> </li> </ol> <ol role="list" start="2"> <li aria-setsize="-1" data-aria-level="1" data-aria-posinset="2" data-font="Arial" data-leveltext="%1)" data-listid="20" role="listitem"> <p paraeid="{1643af60-c312-489d-8381-caa3af30baa0}{222}" paraid="924674236">Heise, N., N.S. De Silva, K. Silva, A.&nbsp;Carette, G.&nbsp;Simonetti, M.&nbsp;Pasparakis&nbsp;&amp;&nbsp;U. Klein.&nbsp;(2014)&nbsp;Germinal&nbsp;center&nbsp;B-cell maintenance and differentiation are controlled by distinct NF-&kappa;B&nbsp;transcription factor subunits.&nbsp;Journal of Experimental&nbsp;Medicine&nbsp;211:2103.&nbsp;</p> </li> </ol> <ol role="list" start="3"> <li aria-setsize="-1" data-aria-level="1" data-aria-posinset="3" data-font="Helvetica,Arial" data-leveltext="%1)" data-listid="20" role="listitem"> <p paraeid="{099c0627-b115-421f-8332-12b293418bf3}{24}" paraid="1961785123">De Silva, N.S.&nbsp;&amp;&nbsp;U. Klein.&nbsp;(2015)&nbsp;Dynamics of B cells in germinal centres.&nbsp;Nature Reviews&nbsp;Immunology&nbsp;15:137.&nbsp;</p> </li> </ol> <p paraeid="{099c0627-b115-421f-8332-12b293418bf3}{24}" paraid="1961785123">This project is part of the&nbsp;<a href="https://medicinehealth.leeds.ac.uk/leeds-institute-research-st-james/doc/international-phd-academy-medical-research">International PhD Academy: Medical Research</a></p> <p paraeid="{099c0627-b115-421f-8332-12b293418bf3}{24}" paraid="1961785123"><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete an <a href="http://www.leeds.ac.uk/info/130206/applying/91/applying_for_research_degrees">online application form</a> and submit this&nbsp;alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates. Please make it clear in the research information section that you are applying for the International PhD Academy: Medical Research, as well as the title of the project you wish to be considered for.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &bull; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &bull; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting LIMRPhD@leeds.ac.uk.</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School Office e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked research areas</h3>