Research Interests

Retinoid Receptors (RARs) in Leukaemogenesis, Targeting Epigenetic Changes in Anti-Leukaemia Therapy

We have shown that retinoic acid (RA) and myelomonocytic growth factors (G-/GM-CSF) co-operatively induce differentiation of some acute myeloid leukaemia (AML) cell lines and cells derived from patients with AML, particularly APL (M3) and M2 subtypes.

Stimulation of AML cell differentiation by ATRA and G-/GM-CSF was associated with induction of RA-responsive gene expression through direct effects on receptor activity. Activation of RAR activity by myelocytic growth factors involved both p38 and ERK MAP kinase signalling. Extending these studies, we discovered that in contrast to normal haemopoietic cells, resistance of some AMLs to differentiation induction by G-/GM-CSF and/or RA is paralleled by lack of expression of primary RA target genes, such as RAR2.

We find that the RAR2 promoter is extensively methylated in AML cells and that pre-treatment of such cells with DNA demethylating agents such as 5-aza-cytydine reverses their resistance to myelomonocytic growth factors and RA at both phenotypic and gene expression levels. These results highlight the potential therapeutic use of epigenetic modifiers like decitabine, which may relieve the negatively acting epigenetic changes that repress genes required for cellular maturation and amplify the effects of differentiation inducers like RA and G-/GM-CSF in AML.

Further studies addressing the mechanisms underlying changes in the chromatin structure of AML cells that render them unresponsive to ATRA are in progress. A better understanding of these mechanisms should unlock the therapeutic response to ATRA in AML.

Molecular Mechanisms of Transcriptional Deregulation in Leukaemia and Lymphoma

Our work on the molecular pathogenesis of acute promyelocytic leukaemia (APL) led to the discovery of histone deacetylase (HDAC) inhibitors as potential therapeutic agents in retinoic acid sensitive and resistant types of this disease. 

Recently we have cloned a cDNA that encodes a novel histone deacetylase (HDAC9), which associates with transcription factors implicated in pathogenesis of myeloid (PLZF, MLL) and lymphoid (TEL, BCL-6) malignancies. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumours and HDAC9 is highly overexpressed in cells derived from patients with non-Hodgkin’s lymphoma. Taken together, our findings suggest an involvement for HDACs in haemopoietic cancers and point out HDAC9 as a possible therapeutic target in B cell malignancies. 

Using experimental models we can demonstrate that overexpression of HDAC9 in B cells does lead indeed to the development of Non-Hodgkins Lymphomas. Further studies are in progress to investigate the mechanisms through which HDAC9 contributes to the development of NHL.

Key Collaborations

National
Professor Mel Greaves
Professor Tariq Enver
Dr David Grimwade

International
Professor Jonathan Licht (Mount Sinai School of Medicine, New York)
Professor Samuel Waxman (Mount Sinai School of Medicine, New York)
Dr Pier Paolo Pandolfi (Memorial Sloan Kettering Cancer Centre, New York)
Professor Zhu Chen (Shanghai Institute of Haematology, China)