WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
Thomas Milne
Canadian
thomas.milne@imm.ox.ac.uk
Present Position
2010 – present
Group Leader, MRC Molecular Haematology Unit (WIMM)
Previous Positions
Nov.2004 – Nov 2010
Postdoctoral Fellow, Dr. C. David Allis, Lab of Chromatin
Biology The Rockefeller University, NY, NY
Sept. 2001 – Nov 2004
Ph.D., awarded May 2005, Supervisor: Dr. Hugh Brock
University of British Columbia, Vancouver, B.C., Co-supervisor:
Dr. Jay Hess, University of Pennsylvania, Philadelphia, PA
Mar 1 2000 – Aug 31 2001
Lab Technician, Dr. Jay Hess, University of Pennsylvania,
Dept. Pathology and Lab medicine.
June 1 1998 – Dec 31 1999 Lab Technician, Dr. Hugh Brock, Zoology, UBC; Dr. Vett Lloyd,
University of Dalhousie; Dr. T.A. Grigliatti, Zoology, UBC.
1995 – 1998
M.Sc., awarded May 1998, Supervisor: Dr. Hugh Brock
University of British Columbia, Vancouver, B.C.
1995
B.Sc. Genetics, 1995, University of British Columbia,
Vancouver, B.C.
Research Achievements
My early interests lead me towards the field of epigenetics with a very specific interest in
chromatin structure and cancer biology. Epigenetics is described as the study of heritable
changes in gene expression that are not due to modifications in the DNA sequence. Posttranslational modifications of histone proteins are considered to be one of the epigenetic
mechanisms that multicellular organisms use in order to guarantee tight spatial and temporal
expression of key genes during development and differentiation. These modifications include
"marks" such as phosphorylation (P), acetylation (Ac), methylation (Me, which can be added
as a mono (1), di (2) or tri (3) methyl mark) and ubiquitination (Ub) which function by
recruiting and/or stabilizing specific effector proteins (also referred to as “reader” proteins).
During my Masters degree with Dr. Hugh Brock, we showed that the polycomb group (PcG)
protein Additional Sex Combs (Asx, aka ASXL, a gene commonly mutated in acute
leukaemias in humans) was functionally linked with activity of trithorax group (TrxG) proteins.
This led directly to my PhD work with Dr. Hugh Brock and Dr. Jay Hess (as my cosupervisor) on the human homolog of the Drosophila Trx protein, MLL. We found that the
MLL SET domain has histone 3 lysine 4 (H3K4) methyltransferase activity that is essential
for its function in maintaining target gene activation. We also found that in leukaemia, MLL
fusion proteins increase methylation of H3K79 on target genes in vivo. H3K79 methylation at
HOX genes has subsequently been recognized as a hallmark of MLL leukaemias. During my
postdoc in Dr. C. David Allis’ lab we showed that recruitment of MLL is a complex
“multivalent engagement” process where no single interaction is necessary or sufficient. As a
group leader at the WIMM, our work has continued on understanding the molecular basis of
MLL leukaemogenesis.
Lay Summary of Research
Despite progress in treating many cancers, children and adults with mutations in the Mixed
Lineage Leukaemia (MLL) gene still have very poor survival rates. This is likely due to the
fact that MLL is a master regulator that modifies the “epigenetic” information content of a cell.
Epigenetics is often defined as altering the inherited gene expression patterns of a cell
without altering the underlying DNA sequence. Thus epigenetic information is not stored in
the DNA itself, but in specialized proteins called histones. It is becoming clear not only that
aberrant epigenetic changes are common in many human diseases such as leukaemia, but
that these changes by their very nature are reversible. A great number of epigenetic cell
memory proteins that have been implicated in human disease have also turned out to be
enzymes that are involved in “writing”, “erasing” or “reading” histone modifications. Effective
therapies are likely to require a cocktail of different inhibitors and will therefore depend on a
clear understanding of how multiple epigenetic proteins cooperate in disease progression.
Readers, writers and erasers are excellent candidates for the development of targeted
therapies that focus on specific activities. The goals of the lab are to understand the
molecular details of how MLL leukaemias rewrite the epigenetic information content of the
cell, and to cooperate with chemists and structural biologists to develop inhibitors that may
one day allow us to develop specialized drugs that will stop MLL leukaemias from growing.
All Publications Over the Past 5 Years
Wilkinson A.C.*, Ballabio E.*,Geng H., North P., Tapia M., Kerry J., Biswas D., Roeder RG,
Allis C.D., Melnick A., de Bruijn M.F.T.R. and Milne T.A. (2013) RUNX1 Is a Key Target
in t(4;11) Leukemias that Contributes to Gene Activation through an AF4-MLL Complex
Interaction. Cell Rep, 3, 116-127.
Ballabio E., Milne T.A. (2012) Molecular and epigenetic mechanisms of MLL1 in human
leukaemogenesis. Cancers, 4, 904-944.
Geng, H.; Brennan, S.; Milne, T.A.; Chen, W.-Y.; Li, Y.; Hurtz, C.; Kweon, S.-M.; Zickl, L.;
Shojaee, S.; Huang, C., et al., (2012) Integrative epigenomic analysis identifies
biomarkers and therapeutic targets in adult b-acute lymphoblastic leukemia. Cancer
Discovery, 2, 1004-1023.
Akalin A., Garrett-Bakelman F.E., Kormaksson M., Busuttil J., Zhang L., Khrebtukova I.,
Milne T.A., Huang Y., Biswas D., Hess J.L., Allis C.D., Roeder R.G., Valk P.J.M.,
Löwenberg B., Delwel R., Fernandez H.F., Paietta E., Tallman M.S., Schroth G.P.,
Mason C.E., Melnick A. and Figueroa M.E. (2012) Base-pair resolution DNA methylation
sequencing reveals profoundly divergent epigenetic landscapes in Acute Myeloid
Leukemia PLoS Genet, 8, e1002781
Kowalczyk M. S., Hughes J.R., Garrick D., Lynch M.D., Sharpe J.A., Sloane-Stanley J.A.,
McGowan S.J., de Gobbi M., Hosseini M., Vernimmen D., Brown J.M., Gray N.E.,
Collavin L., Gibbons R.J., Flint J., Taylor S., Buckle V.J., Milne T.A., Wood W.G. &
Higgs D.R. (2012) Intragenic enhancers act as alternative promoters. Mol Cell, 45, 447458.
Biswas, D., Milne, T.A., Basrur, V., Kim, J., Elenitoba-Johnson, K.S., Allis, C.D. & Roeder,
R.G. (2011) Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins
through distinct partner protein complexes. Proc Natl Acad Sci U S A, 108, 15751-15756.
Ruthenburg, A.J., Li, H., Milne, T.A., Dewell, S., McGinty, R.K., Yuen, M., Ueberheide, B.,
Dou, Y., Muir, T.W., Patel, D.J. & Allis, C.D. (2011) Recognition of a Mononucleosomal
Histone Modification Pattern by BPTF via Multivalent Interactions. Cell, 145, 692-706.
Milne, T.A., Kim, J., Wang, G.G., Stadler, S.C., Basrur, V., Whitcomb, S.J., Wang, Z.,
Ruthenburg, A.J., Elenitoba-Johnson, K.S., Roeder, R.G. & Allis, C.D. (2010) Multiple
interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in
leukemogenesis. Mol Cell, 38, 853-863.
Wang, Z., Song, J., Milne, T.A., Wang, G.G., Li, H., Allis, C.D. & Patel, D.J. (2010) Pro
isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and
HDAC-mediated repression. Cell, 141, 1183-1194.
Ferris, A.L., Wu, X., Hughes, C.M., Stewart, C., Smith, S.J., Milne, T.A., Wang, G.G., Shun,
M.C., Allis, C.D., Engelman, A. & Hughes, S.H. (2010) Lens epithelium-derived growth
factor fusion proteins redirect HIV-1 DNA integration. Proc Natl Acad Sci U S A, 107,
3135-3140.
Hunter, R.G., McCarthy, K.J., Milne, T.A., Pfaff, D.W. & McEwen, B.S. (2009) Regulation of
hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci U
S A, 106, 20912-20917.
Milne, T.A., Zhao, K. & Hess, J.L. (2009) Chromatin immunoprecipitation (ChIP) for analysis
of histone modifications and chromatin-associated proteins. Methods Mol Biol, 538, 409423.
Kim, J., Guermah, M., McGinty, R.K., Lee, J.S., Tang, Z., Milne, T.A., Shilatifard, A., Muir,
T.W. & Roeder, R.G. (2009) RAD6-Mediated transcription-coupled H2B ubiquitylation
directly stimulates H3K4 methylation in human cells. Cell, 137, 459-471.
Caslini, C., Yang, Z., El-Osta, M., Milne, T.A., Slany, R.K. & Hess, J.L. (2007) Interaction of
MLL amino terminal sequences with menin is required for transformation. Cancer Res,
67, 7275-7283.
Ten Key Publications Throughout your Career
Milne, T.A., Kim, J., Wang, G.G., Stadler, S.C., Basrur, V., Whitcomb, S.J., Wang, Z.,
Ruthenburg, A.J., Elenitoba-Johnson, K.S., Roeder, R.G. & Allis, C.D. (2010) Multiple
interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in
leukemogenesis. Mol Cell, 38, 853-863.
Dou, Y., Milne, T.A., Ruthenburg, A.J., Lee, S., Lee, J.W., Verdine, G.L., Allis, C.D. &
Roeder, R.G. (2006) Regulation of MLL1 H3K4 methyltransferase activity by its core
components. Nat Struct Mol Biol, 13, 713-719.
Wysocka, J., Swigut, T., Xiao, H., Milne, T.A., Kwon, S.Y., Landry, J., Kauer, M., Tackett,
A.J., Chait, B.T., Badenhorst, P., Wu, C. & Allis, C.D. (2006) A PHD finger of NURF
couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature, 442, 8690.
Milne, T.A., Martin, M.E., Brock, H.W., Slany, R.K. & Hess, J.L. (2005) Leukemogenic MLL
fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription
and multiple histone modifications. Cancer Res, 65, 11367-11374.
Dou, Y., Milne, T.A., Tackett, A.J., Smith, E.R., Fukuda, A., Wysocka, J., Allis, C.D., Chait,
B.T., Hess, J.L. & Roeder, R.G. (2005) Physical association and coordinate function of
the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell, 121,
873-885.
Wysocka, J., Swigut, T., Milne, T.A., Dou, Y., Zhang, X., Burlingame, A.L., Roeder, R.G.,
Brivanlou, A.H. & Allis, C.D. (2005) WDR5 associates with histone H3 methylated at K4
and is essential for H3 K4 methylation and vertebrate development. Cell, 121, 859-872.
Milne, T.A., Hughes, C.M., Lloyd, R., Yang, Z., Rozenblatt-Rosen, O., Dou, Y., Schnepp,
R.W., Krankel, C., Livolsi, V.A., Gibbs, D., Hua, X., Roeder, R.G., Meyerson, M. & Hess,
J.L. (2005) Menin and MLL cooperatively regulate expression of cyclin-dependent kinase
inhibitors. Proc Natl Acad Sci U S A, 102, 749-754.
Martin, M.E., Milne, T.A., Bloyer, S., Galoian, K., Shen, W., Gibbs, D., Brock, H.W., Slany,
R. & Hess, J.L. (2003) Dimerization of MLL fusion proteins immortalizes hematopoietic
cells. Cancer Cell, 4, 197-207.
Milne, T.A., Briggs, S.D., Brock, H.W., Martin, M.E., Gibbs, D., Allis, C.D. & Hess, J.L.
(2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol
Cell, 10, 1107-1117.
Markers of Esteem
Canadian Institutes of Health Research (CIHR) Fellowship July1/05 to July1/08
Current Grant Support
1) MRC Unit Award 2012-2017 £29M
2) Children with Cancer UK, Epigenetic mechanisms of MLL-AF4 leukaemogenesis:
£48,104