Professor Brian Huntly
Leukaemia stem cell biology and leukaemogenesis
Email: bjph2@cam.ac.uk | Departmental Affiliation: Haematology
Research
Plain English: Our group is interested in the interface between normal and malignant haematopoietic stem cell biology. Comparisons of these systems will allow us to determine how normal regulatory mechanisms are corrupted to generate haematological malignancies. We use experimental model systems and patient samples to answer these questions. This information will provide the basis for targeted therapies to improve the often dismal treatment outcomes for haematological cancers.
Research Focus: Leukaemias have been demonstrated to be wholly dependent upon a small population of so-called cancer stem cells. These cells represent the critical targets for cancer treatment and a greater understanding of their biology and its interface with normal stem cell function is fundamental to improving treatment outcomes.
The focus of the Huntly laboratory is on this interface. They use a combination of techniques in cell lines, animal models and primary human tissue to dissect stem cell function. The aim is to understand how normal stem cell function is corrupted during the evolution and maintenance of cancer and how these processes might be therapeutically targeted to improve the outcome in haematological malignancies. They are examining the role of mutations that occur in and alter the role of haematopoietic stem and progenitors. Many of these mutations alter epigenetic regulation, enhancer function and transcriptional and metabolic programmes and these are all ongoing areas of investigation within the lab.
Much of the lab’s research focuses on lymphoma and acute myeloid leukaemia (AML), a disease with dismal five-year survival rates and urgent clinical need for new treatment options. Therapeutically, their work includes the identification of the Bromodomain and extra terminal (BET) proteins as critical mediators of leukaemia stem cells in AML and the development of an inhibitor of these proteins in a Phase I/II clinical trial in relapsed blood cancers.
Model of mechanisms and stage specific nature of Crebbp tumour suppression in lymphoid malignancies. Following early loss of Crebbp activity in the HSPC compartment, abnormal epigenetic regulation, post-translational modifications of substrate proteins and altered transcription lead to expansion of lymphoid progenitors, blocked differentiation, increased proliferation and clonogenicity within this expanded progenitor pool. In association with an alteration of the DNA damage response mediated through suboptimal Crebbp acetylation of p53, DNA double strand breaks accumulate and accompanied by a relative decrease in apoptosis, lead to the retention of mutations within B-cell progenitors. We illustrate the epigenetic priming of specific loci at earlier time points, where H3K27ac CHIP-seq and RNA-seq at the critical gene X locus read out in terms of downregulation of gene expression only at later timepoints during lymphoma evolution. We speculate that the molecular aberrations cumulatively acquired interact with this primed epigenetic state and lead to the restoration of self-renewal in this abnormal pre-malignant stem cell population and to the evolution of lymphoma.
Huntly Group photo
Key Publications
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Lara-Astiaso D, Goñi-Salaverri A, ... Huntly BJP. In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis. Nat Genet. 2023 Sep;55(9):1542-1554. PMCID: PMC10484791
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Agrawal-Singh S, Bagri J, ... Huntly BJP. HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia. Blood. 2023 Apr 6:blood.2022016528. PMCID: PMC10113176
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Yun H, Narayan N, Vohra S, Giotopoulos G, Mupo A, Madrigal P, Sasca D, Lara-Astiaso D, Horton SJ, Agrawal-Singh S, Meduri E, Basheer F, Marando L, Gozdecka M, Dovey OM, Castillo-Venzor A, Wang X, Gallipoli P, Müller-Tidow C, Osborne CS, Vassiliou GS, Huntly BJP. Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression. Nat Genet. 2021 Oct;53(10):1443-1455. PMCID: PMC7611829
- Sasca D, Yun H, Giotopoulos G, Szybinski J, Evan T, Wilson NK, Gerstung M, Gallipoli P, Green AR, Hills R, Russell N, Osborne CS, Papaemmanuil E, Göttgens B, Campbell P, Huntly BJP. Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies. Blood. 2019 Dec 12;134(24):2195-2208. PMCID: PMC7484777
- Gozdecka M, Meduri E, Mazan M, Tzelepis K, Dudek M, Knights AJ, Pardo M, Yu L, Choudhary JS, Metzakopian E, Iyer V, Yun H, Park N, Varela I, Bautista R, Collord G, Dovey O, Garyfallos DA, De Braekeleer E, Kondo S, Cooper J, Göttgens B, Bullinger L, Northcott PA, Adams D, Vassiliou GS, Huntly BJP. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nat Genet. 2018 Jun;50(6):883-894. PMCID: PMC6029661
- Horton SJ, Giotopoulos G, Yun H, Vohra S, Sheppard O, Bashford-Rogers R, Rashid M, Clipson A, Chan WI, Sasca D, Yiangou L, Osaki H, Basheer F, Gallipoli P, Burrows N, Erdem A, Sybirna A, Foerster S, Zhao W, Sustic T, Petrunkina Harrison A, Laurenti E, Okosun J, Hodson D, Wright P, Smith KG, Maxwell P, Fitzgibbon J, Du MQ, Adams DJ, Huntly BJP. Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors. Nature Cell Biology. 2017 Sep;19(9):1093-1104. PMID: 28825697 PMCID:PMC5633079
- Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ*, Kouzarides T*. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011 478(7370):529-33 *joint senior authors PMCID:PMC3679520
- Huntly BJP, Shigematzu H, Deguchi K, Lee BH, Mizuno S, Duclos N, Rowan R, Amaral S, Curley D, Williams IR, Akashi K, Gilliland DG. MOZ-TIF2, but not BCR-ABL, confers properties of leukaemic stem cells to committed murine haematopoietic progenitors. Cancer Cell. 2004; 6: 586-595 PMID:15607963