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June 12-13, 2019 | Edinburgh, Scotland
8th European Clinical Microbiology and Immunology Congress
&
3rd World congress on Biotechnology
Joint Event
Microbiology: Current Research | Volume: 3 | ISSN: 2591-8036
Notes:
Deciphering the role of fibroblasts and macrophages in bone marrow mediated
chemotherapy resistance in acute myeloid leukaemia
Mark Williams 1,2, Barbara McCrorie1, Abigail Macleod1, Scott Davidson2, Gregor McMurray 3, Chris Estell4,
Joanne Hanney5, Carl Goodyear6, Gerard Graham 6, Helen Wheadon6 and Monica Guzman7
1 Glasgow Caledonian University, UK
2 University of Strathclyde, UK
3 NHS Greater Glasgow and Clyde, UK
4 University of Exeter, UK
5 NHS Ayrshire and Arran,
6 University of Glasgow, UK
7 Cornell University, USA
A cute Myeloid Leukaemia (AML) is one of the most
pressing unmet clinical need in the haematology field.
For themajority of AML patient’s survival is between 5-20%.
Chemoresistance is a major contributing factor towards
inferior survival in AML, which is significantly influenced
by the bone marrow microenvironment (BMME).
Within the BMME, AML cells interact with stromal (e.g.
fibroblasts) and immune cells (e.g. macrophages [Mφs]),
with a well-established role for these cells impacting upon
chemoresistance in blood cancers, including Multiple
Myeloma.
The study objectives were to ascertain the role played by
fibroblasts and Mφs in conferring protection of AML cells
from cell death induced by traditional chemotherapeutics
and a multi-cyclin-dependent kinase/myeloid cell
leukaemia 1 inhibitor (multi- CDKi/MCL1 i) AML cells and
determine the molecular mechanism(s) underlying this
chemoresistance.
U937 cells were incubated with normal media (NM) or
conditioned media from the human BM fibroblast cell line
HS5 (HS-CM) or primary Mφs (Mφ-CM). The U937 cells
were then exposed to daunorubicin/doxorubicin (1mM) or
the multi-CDKi/MCL1i (0-10 mM) for 24h. HS-CM and Mφ-
CM significantly protected U937 cells from the effects of
the daunorubicin/doxorubicin and the multi-CDKi/MCL1i.
HS-CM and Mφ-CM activated various pro-survival and
anti-apoptotic pathways in U937 cells including the ERK1/2
and MCL-1 pathways respectively. Initial studies suggest
that treatment of U937 cells with the MEK1/2 inhibitor
selumetinib re-sensitised the U937 cells to the multi-CDKi/
MCL1i in the context of HS-CM.
These findings demonstrate that combining a novel multi-
CDKi/MCL1i with selumetinib may overcome fibroblast
elicited chemoresistance and may represent a promising
therapeutic approach for AML.
Speaker Biography
Mark Williams qualified with a BSc (Hons) in immunology and
pharmacology from the University of Strathclyde in 2006. He was then
awarded a PhD in immunobiology from Queen’s University Belfast
in 2010, where he conducted studies investigating the impact of
different CFTR mutations on inflammation in cystic fibrosis. He then
conducted his postdoctoral research studies in acute lymphoblastic
leukaemia and multiple myeloma at the University of Glasgow from
2010-2016. He obtained his lectureship in cell and molecular biology at
Glasgow Caledonian University in 2017, in which his research focuses
on modelling and therapeutically targeting leukaemia-bone marrow
microenvironment interactions in acute myeloid leukaemia. He has
published papers in high impact journals including blood and he is also
a reviewer for the open access Journal Cancer Drug Resistance, as well
as research grants for the Glasgow Children’s Hospital Charity and the
Carnegie Trust.
e:
Mark Williams et al., Microbiol Curr Res, Volume 3
ISSN: 2591-8036