Unravelling clinical heterogeneity in Philadelphia positive Acute Lymphoblastic Leukaemia
Background: The Philadelphia (Ph) chromosome results in the BCR-ABL fusion oncoprotein with enhanced tyrosine kinase activity. It is a high-risk cytogenetic abnormality found in approximately 5% of childhood and 24% of adult acute lymphoblastic leukaemia (ALL) and all patients with chronic myeloid leukaemia (CML). Recent reports indicate that Ph+ALL can be further sub-divided into a true lymphoid leukaemia with acquisition of the BCR-ABL oncogene in a committed B-cell progenitor (standard Ph+ALL), CML-like Ph+ ALL with BCR-ABL present in earlier multipotent progenitors. We hypothesise that CML-like and standard Ph+ALL differ transcriptionally and by cell-of-origin, resulting in different responses to therapy, particularly with respect to presence of drug-resistant stem or progenitor cells.
Project aims: The overall aim of the project is to identify cellular and molecular signatures of the 3 Ph+ALLs, namely lymphoid blast phase CML, CML-like Ph+ALL, and B cell Ph+ALL in order to develop useful tools to identify the subtypes clinically.
The project has three main objectives:
1. To discover whether CML and CML-like Ph+ALL originate in the same types of primitive blood cells located in the bone marrow. This will help us understand how CML-like Ph+ALL develops.
2. To measure the levels of gene expression in the different leukaemia subtypes to identify genetic ‘signatures’ that may allow the different subtypes to be identified at time of diagnosis.
3. To test CML, CML-like Ph+ALL, and Ph+ALL cells with targeted therapies derived from aim 2 to derive potential novel therapies for this patient group.
In this way, we aim to improve the outlook for patients diagnosed with Ph+ALL to ensure they get the right diagnosis and treatment.
Laboratory techniques: During the PhD, students will become familiar with culture of cell lines and primary cells, drug treatment evaluation with apoptosis, cell cycle and cell proliferation assays, and both in vitro and in vivo haematopoietic stem and progenitor cell assays. Flow cytometry, bulk and single cell gene expression, and FISH will also be used.
Specifications: The successful applicant will have a strong interest in exploring therapeutic strategies for blood cancers/acute lymphoblastic leukaemia, and hold a minimum of a first degree (2:1) or above, ideally in cell biology, biochemistry or molecular biology. Experience in molecular biology (e.g. immunoblotting, qPCR and flow cytometry), or cell culture techniques (e.g. culturing cell lines/primary cells), would be an advantage.