Molecular Biology of CML

Junia V. Melo and her group have a longstanding interest in the molecular mechanisms underlying the malignant phenotype of chronic myeloid leukaemia (CML). This is a disorder of the haemopoietic stem cell which usually starts as a relatively ‘benign’ leukaemia (chronic phase), but invariably progresses to an acute transformation or blast crisis. CML and 20% of adult acute lymphoblastic leukaemias (ALL) are caused by a reciprocal translocation between chromosomes 9 and 22, whose main functional product is the BCR-ABL hybrid gene, located on the Philadelphia (Ph) chromosome. BCR-ABL encodes an oncogenic fusion protein with a constitutively activated tyrosine kinase domain. The work in Professor Melo’s group is ultimately focused on understanding how this biochemical abnormality is translated into the cellular and clinical manifestations of CML and Ph+ ALL. These studies have been facilitated over the past 5 years by the availability of imatinib mesylate (formerly STI571), a Bcr-Abl tyrosine kinase inhibitor which is now being successfully used for the treatment of Ph+ leukaemias. Professor Melo’s team was one of the first to contribute important pre-clinical data characterising the response of CML cells to imatinib, and to identify the possible mechanisms for development of resistance to the drug in advanced stages of CML. The current areas of investigation in her group are:

Identification of genes transcriptionally regulated by Bcr-Abl: this has been carried out in various haemopoietic cellular systems by means of RNA differential display (DD) and, more recently, using microarray technology. The genes identified through these screenings are then characterised in individual projects as for their relevance to the pathogenesis of CML and suitability as possible new therapeutic targets.

Resistance to imatinib mesylate: this work aims at identifying the mechanisms of clinical resistance to imatinib, to develop tests for prediction of response and resistance to this drug, and to evaluate alternative combination chemotherapeutic regimens for patients relapsing on imatinib treatment.

Genomic instability in CML: the objective of this project is to determine whether environmental and/or genetic factors predispose to the formation of the BCR-ABL fusion gene, or facilitate the emergence of additional mutations which underlie the progressive acute transformation of CML.

Gene transfer/therapy in CML (in collaboration with Dr Jane Apperley): this project aims at establishing the appropriate conditions for efficient and safe gene transfer into normal and leukaemia cells for genetic marking and therapeutic purposes. Various pre-clinical studies are currently being developed. A clinical trial of donor lymphocytes transduced with a 'suicide gene' for the treatment of graft-versus-host disease after stem cell transplantation is due to start soon.

The research group

Melo Group Photo May 06

From left to right, Back row: Dr. Manuel S. Simões, Ms. Tamara Law, Ms. Daniela Passos, Mr. Daniel Sears, Mr. Eugenio Macchiarulo, Ms. Eva Moravcsik, Dr. Steve Hart, Ms. Ana Elisa B. Silva.

Front row: Ms. Kathryn Tran, Dr. Maria Makri, Prof. Junia V. Melo, Mr. James Morris, Prof. Jane Apperley, Dr. David Barnes, Dr. Mohamad Mohty.