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allied
academies
August 23-24, 2018 | London, UK
Hematology and Oncology
2
nd
International Conference on
Journal of Hematology and Blood Disorder | Volume 2
Intracellular oxidative stress contributes to the oncogenic potential of mutant FLT3 in acute myeloid
leukaemia patients, and is a synergistic treatment target
M D Dun
NSW, Australia
L
eukaemic transformation of haematopoietic progenitors is
a multistage process characterised by the overproduction
of reactive oxygen species (ROS). AML patients diagnosed
with recurring mutations to the FMS-like tyrosine kinase-3
(FLT3) commonly relapse after they achieve initial remission,
succumb to a treatment resistant AML. FLT3-ITD (Internal
TandemDuplication) mutations are themost common genomic
driver lesion, and are associated with the overproduction of
ROS. Overproduction of ROS is induced by the activation of
alternative metabolic pathways causing increased genomic
instability through the oxidation of DNA bases, influencing
clonal evolution. Importantly, ROS oxidises and inactivates key
proteins indispensable for the regulation of growth and survival
signalling pathways. To determine the cooperative mechanisms
underpinning leukaemogenic growth and survival signalling,
bone marrow trephine biopsies from AML patients at diagnosis
were subjected high-resolution quantitative proteomic,
phosphoproteomic and REDOX sequencing. Patients expressing
FLT3-ITD mutations showed significantly increased expression
of proteins directly responsible for the production of ROS.
Oxidation and inactivation of tumour suppressor proteins
particularly, protein tyrosine phosphatases (PTPs) directly
downstream of FLT3, and directly upstream of STAT5 were
seen compared to AML patients expressing wild-type FLT3.
Proteins important in maintaining cellular homeostasis, such as
antioxidants were differentially dysregulated between patient
subtypes supporting the notion of REDOX dysfunction in FLT3-
ITD+ AML patients. Reducing intracellular oxidative stress levels
using novel clinically relevant compounds, reactivated intrinsic
cellular defence systems, inducing selectively synergistic cell
death when combined with FLT3-ITD inhibitors currently in
clinical trials. Importantly, analysis of AML cells grown under
conditions mimicking the bone marrow microenvironment,
enhanced the anti-leukaemic efficacy of our novel therapies
by reducing oxidative stress, decreased oncogene addition,
highlighted the divergent metabolic requirements of AML blast
cells in the bone marrow compared to the circulation. These
studiessuggestamechanismofcooperationbetweenoncogenic
kinases, metabolism and oxidative stress to reveal a novel
treatment paradigm currently under preclinical evaluation.
e:
Matt.Dun@newcastle.edu.au