WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Introduction

Human acute myeloid leukaemias (AMLs) are heterogeneous with respect to both genetics and the function of the cells that make up the disease. A minority of the cells are leukaemia stem cells (LSCs) which have the ability to self-renew for an extended if not indefinite period, thus maintaining and expanding the disease. In order to cure a patient these cells must be eliminated completely, because if they are not they have the ability to regenerate the disease and induce relapse.

Understanding the cellular mechanisms that regulate the self-renewal of the LSC compartment represents a critical current problem in leukaemia biology. The Leukaemia Biology group is focused on understanding the biology of disordered LSCs in comparison with normal haematopoietic stem cells (HSCs) in a range of distinct categories of haematological malignancy, in order to identify new genes and cellular pathways that are critical for LSC function and which could be targeted by new treatments.

A particular area of interest is the burgeoning field of epigenetics. The group has recently discovered a new candidate therapeutic target in the mixed lineage leukaemia subtype of AML, called lysine specific demethylase 1 (LSD1). Working with the Drug Discovery Unit at the CRUK Manchester Institute and industrial partners (Oryzon Genomics and Roche) we synthesised novel compounds that inhibit the enzyme and showed they induce differentiation of LSCs in pre-clinical models. In early phase clinical trials in Manchester and Barcelona we also found that LSD1 inhibitors promote differentiation of blast cells in patients with acute leukaemia.

We have also recently uncovered a novel and frequent oncogenic mechanism in human acute myeloid leukaemia, active in 20% of patients. This is the tissue inappropriate mis-expression of a mesenchymal transcription factor called FOXC1. Expression of FOXC1 in bone marrow cells contributes to the differentiation block which is a cardinal feature of the disease. Developing therapies that target this transcription factor may benefit patients with high level FOXC1 expression.

Selected Publications

Maiques-Diaz A, Spencer GJ, Lynch JT, Ciceri F, Williams EL, Amaral FMR, Wiseman DH, Harris WJ, Li Y, Sahoo S, Hitchin JR, Mould DP, Fairweather EE, Waszkowycz B, Jordan AM, Smith DL, Somervaille TCP. (2018)
Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia.
Cell Reports 22(13):3641-3659. PubMed abstract

Somerville TDD, Simeoni F, Chadwick JA, Williams EL, Spencer GJ, Boros K, Wirth C, Tholouli E, Byers RJ, Somervaille TCP. (2018)
Derepression of the iroquois homeodomain transcription factor gene IRX3 confers differentiation block in acute leukemia.
Cell Reports 22(3):638-652. PubMed abstract

Wiseman DH, Williams EL, Wilks DP, Sun Leong H, Somerville TD, Dennis MW, Struys EA, Bakkali A, Salomons GS, Somervaille TC. (2016)
Frequent reconstitution of IDH2 R140Q mutant clonal multilineage hematopoiesis following chemotherapy for acute myeloid leukemia.
Leukemia 30:1946-1950. Article

Somerville TD, Wiseman DH, Spencer GJ, Huang X, Lynch JT, Leong HS, Williams EL, Cheesman E, Somervaille TC. (2015)
Frequent derepression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukaemia. Cancer Cell 14:329-342. PubMed abstract

Wiseman DH, Struys EA, Wilks DP, Clark CI, Dennis MW, Jansen EE, Salomons GS, Somervaille TC. (2015)
Direct comparison of quantitative digital PCR and 2-hydroxyglutarate enantiomeric ratio for IDH mutant allele frequency assessment in myeloid malignancy.
Leukemia 29:2421-23. Article

Jude JG, Spencer GJ, Huang X, Somerville TD, Jones DR, Divecha N, Somervaille TC. (2015)
A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.
Oncogene 34:1253-1262. PubMed abstract

Wiseman DH, Small HF, Wilks DP, Waddell ID, Dennis MW, Ogilvie DJ, Somervaille TC. (2014)
Elevated plasma 2-hydroxyglutarate in acute myeloid leukaemia: association with the IDH1 SNP rs11554137 and severe renal impairment.
British Journal of Haematology 166:145-148. Abstract

Huang X, Spencer GJ, Lynch JT, Ciceri F, Somerville TD, Somervaille TC. (2014)
Enhancers of Polycomb EPC1 and EPC2 prevent accumulation of MYC and sustain the oncogenic potential of MLL leukemia stem cells.
Leukemia 28:1081-1091. PubMed abstract

Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, Miller CJ, Ogilvie DJ, Somervaille TC. (2012)
The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells.
Cancer Cell 21:473-487. PubMed abstract

Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. (2008)
Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.
Nature 405:1205-1209. PubMed abstract