Mechanisms of myeloid leukaemogenesis and leukaemia stem cell biology
The aims of our group are to interrogate mechanisms of leukaemogenesis, particularly myeloid disease, and leukaemia stem cell (LSC) biology, using analysis of mouse and cellular based model systems and of primary human normal and leukaemia cells. In particular, we aim to determine the degree of functional overlap between normal haematopoietic stem cells (HSCs) and LSCs at the molecular level, and identify pathways that are differentially utilised in leukaemia stem cells and that may be tested as therapeutic targets. There are currently two major areas of research focus within the lab. The first centres on the mechanisms of aberrant transcriptional regulation and epigenetic function that accompanies LSC formation and leukaemogenesis, mainly utilising acute myeloid leukaemia (AML) as a disease that exemplifies this process. The second related area of focus is to utilise this knowledge to identify therapeutic targets and to validate novel therapeutics in optimised and relevant pre-clinical studies in vitro and in vivo, with the aim of moving these studies into early phase clinical trials.
Aberrant transcriptional regulation and epigenetic function in AML
An evolving paradigm in myeloid malignancies is transcriptional dysregulation, and many of the mutations that occur in myeloid leukaemias and other haematological malignancies involve transcriptional and epigenetic regulators. Dissection of the shared and specific mechanisms downstream of oncogenes that alter normal transcriptional control in HSCs is the major focus of the lab. We have a number of projects ongoing that address the regulation of transcription in normal HSCs and how this process is subverted in AML and other haematological malignancies. These include: dissecting the functions of epigenetic regulators such as CBP in normal HSC and LSC function, where CBP may function as both an oncogenic activator and a tumour suppressor; the analysis of aberrant epigenetic regulation at chromatin via the bromodomain and extra terminal (BET) proteins in AML; the role of enhancer remodelling in the step-wise generation of leukaemogenic transcriptional programmes, using murine models and human cells; and investigation of the role of the HMG-box gene SOX4, which we believe to be a critical AML target gene.
Identification and pre-clinical validation of therapeutic targets
We and others have recently identified inhibitors of bromodomain and extraterminal domain (BET) protein inhibitors as promising pre-clinical therapeutics in AML and other haematological malignancies. We continue to probe the mechanisms of action of BET inhibitor sensitivity in specific AML subtypes and, together with GSK, we are currently performing a Phase I clinical trial of BET inhibitors in relapsed haematological malignancies with additional translational studies. We are also studying mechanisms of action, pre-clinical efficacy and potential mechanisms of resistance of a number of other inhibitors of epigenetic readers, writers and eraser proteins thought to be important for leukaemogenesis.
Brian Huntly, whose lab is based in the CIMR, is a principal investigator of the Cambridge Stem Cell Institute (SCI) and will relocate to a new SCI building in 2018.
Dawson, M. A., Gudgin, E. J., Horton, S. J., Robson, S., Osaki, H., Giotopulos, G., Putwain, S., Cannizarro, E., Weiss, M., Craig, J., Dittmann. A., Lugo. D., Jeffries, P., Drewes, G., Prinjha, R. K., Kouzarides, T., Vassiliou, G. S. and Huntly, B. J. P. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in Acute Myeloid Leukemia. Leukemia 28, 311–320 (2014).
Diffner, E., Beck,D., Gudgin, E., Thoms, J. A. I., Knezevic, K., Lim, W. K., Boelen, L., Metzeler, K. H., Bohlander, S. K., Buske, C., Olivier, J., Göttgens, B., Wong, J. W., Huntly, B. J. P.* and Pimanda, J. E.*. Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia. Blood 121, 2289–2300 (2013). *joint senior authors
Dawson, M. A., Prinjha, R. K., Dittmann, A., Giotopoulos, G., Bantscheff, M., Chan, W. I., Robson, S. C., Chung, C. W., Hopf, C., Savitski, M. M., Huthmacher, C., Gudgin, E., Lugo, D., Beinke, S., Chapman, T. D., Roberts, E. J., Soden, P. E., Auger, K. R., Mirguet, O., Doehner, K., Delwel, R., Burnett, A. K., Jeffrey, P., Drewes, G., Lee, K., Huntly, B. J.* and Kouzarides, T*. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011) *joint senior authors
Chan, W. I., Dawson, M. A., Hannah, R., Paul, D., Pridans, C., Joshi, A., Gottgens, B., Van Deursen, J. and Huntly, B. J. P. The transcriptional coactivator Cbp controls hematopoietic stem cell quiescence and multipotential differentiation. Mol. Cell. Biol. 31, 5046–5060 (2011).
Anand, S., Stedham, F. E., Beer, P. A., Gudgin, E., Bench, A. J., Green, A. R. and Huntly, B. J. P. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood 118, 1610–1621 (2011).
van der Weyden, L., Giotopolous, G., Rust, A. G., Matheson, L., van Delft, F., Kong, J., Corcoran, A., Huntly, B. J.* and Adams, D. J.*. Modeling the evolution of ETV6-RUNX1-induced B-cell precursor acute lymphoblastic leukemia in mice. Blood 118, 1041–1051 (2011). *joint senior authors
Anand, S., Stedham, F. E., Gudgin, E., Beer, P. A., Bench, A. J., Erber, W., Green, A. R. and Huntly, B. J. P. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood 118, 177–181 (2011).
Kvinlaug, B. T., Chan, W. I., Bullinger, L., Sears, C., Paul, D., Okabe, R., Lee, B. H., Benner, A., De Silva, I., Valk, P., Delwel, R., Armstrong, S. A., Döhner. H., Gilliland, D. G. and Huntly, B. J. P. Common and overlapping pathways contribute to the evolution of acute myeloid leukaemias. Cancer Res. 71, 4117–4129 (2011).
Li, P., Burke, S., Chen, X., Ortiz, M., Lee, S.-C., Lu, D., Campos, L., Dougan, G., Huntly, B. J. P., Gottgens, B., Jenkins, N., Copeland, N. C., Colucci, F. and Liu, P. Reprogramming of T Cells to Natural Killer-like Cells upon Bcl11b Deletion. Science 329, 85–89 (2010).
Vezzoli, A., Bonadies, N., Allen, M. D., Freund, S. M., Santiveri, C. M., Kvinlaug, B. T., Huntly, B. J., Göttgens, B. and Bycroft, M. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nature Struct. Mol. Biol. 17, 617–619 (2010).
Zhao, R., Follows, G. A., Beer, P. A., Huntly, B. J. P., Green, A. R. and Alexander, D. R. Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders N. Engl. J. Med. 359, 2778–2789 (2008).
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Catrillion, D., Passegue, E., Cullen, D., McDowell, E., Lazo-Kallanian, S., Williams, I., DePinho, R. and Gilliland, D. G. FoxO are critIcal mediators of stem cell resistance to physiologic oxidative stress Cell 128, 325–339 (2007).
Lee, B. H., Tothova, Z., Levine, R. L., Anderson, K., Cullen, D. E., McDowell, E. P., Adelsperger, J., Huntly, B. J. P., Beran, M., Jacobsen, S. E. and Gilliland, D. G. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell 12, 367–380 (2007).
Bansal, D., Scholl, C., Frohling, S., McDowell, E., Lee, B. H., Dohner, K., Ernst, P., Davidson, A., Daley, G. Q., Zon, L. I., Gilliland, D. G. and Huntly, B. J. P. Cdx4 upregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model. Proc. Natl Acad. Sci. USA 103, 16924–16929 (2006).
Levine, R. L., Wadleigh, M., Cools, J., Ebert, B. L., Wernig, G., Huntly, B. J. P., Boggon, T. J., Wlodarska, I., Clark, J. J., Moore, S., Adelsberger, J., Koo, S., Lee, J., Gabriel, S., Marynen, P., Vandenberghe, P., Mesa, R. A., Tefferi, A., Griffin, J. D., Eck, M. J., Sellers, W. J., Meyerson, M., Golub, T. R., Lee, S. J. and Gilliland, D. G. Activating Mutation in the Tyrosine Kinase JAK2 in Polycythemia Vera, Essential Thrombocythemia and Myeloid Metaplasia with Myelofibrosis. Cancer Cell 7, 387–397 (2005).
Weisberg, E., Manley, P W., Breitenstein, W., Brüggen, J., Cowan-Jacob, S.W., Ray, A. Huntly, B.J.P., J. Callahan, L. Fabbro, D. Fendrich, G. Hall-Meyers, E. Kung, A. Mestan, J. Neuberg, D. Gilliland, D.G. and Griffin, J.D. AMN107: Characterization of a novel inhibitor of both wild-type and mutant Bcr-Abl in vitro and in murine models of leukaemia. Cancer Cell 7, 129–141 (2005).
Huntly, B. J. P., Shigematzu, H., Deguchi, K., Lee, B. H., Mizuno, S., Duclos, N., Rowan, R., Amaral, S., Curley, D., Williams, I. R., Akashi, K. and Gilliland, D. G. MOZ-TIF2, but not BCR-ABL, confers properties of leukaemic stem cells to committed murine haematopoietic progenitors. Cancer Cell 6, 586–595 (2004).
Dawson, M. A., Kouzarides, T. and Huntly, B. J. P. Targeting epigenetic readers in hematological malignancies. N. Engl J. Med. 367, 647–657 (2012).
Chan, W. I. and Huntly, B. J. P. Leukaemia stem cells in AML. Semin. Oncol. 34, 326–335 (2008).
Huntly, B. J. P. and Gilliland, D. G. Leukemia Stem Cells and the Evolution of Cancer Stem Cells. Nature Rev. Cancer 5, 311–321 (2005).