Role of Jmjd6 in normal and malignant haematopoiesis
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Date
08/07/2017Item status
Restricted AccessRestricted Access
Embargo end date
31/12/2100Author
Sepúlveda, Catarina
Metadata
Abstract
The finely tuned regulation of haematopoietic stem and progenitor cells (HSPCs) is
crucial to sustain normal haematopoiesis. The disruption of the balance between the
quiescence state of haematopoietic stem cells (HSCs) and the
proliferation/differentiation programs that are necessary to meet daily haematopoietic
demands and respond to external insults, can lead to malignant transformation, such
as acute myeloid leukaemia (AML). Therefore, it is essential to investigate the
players that are responsible to maintain haematopoietic homeostasis, so that novel
therapeutic targets can be identified.
HSCs reside in a hypoxic environment that is crucial for their maintenance, as it
protects them from over-proliferation and exhaustion. The response to a limited
availability of oxygen is critically mediated by a transcription factor - hypoxia
inducible factor (HIF). HIF is predominantly regulated by prolyl hydroxylases
(PHDs) that are 2-oxoglutarate (2OG) dependent oxygenases. This superfamily of
oxygen-sensing enzymes has been assigned important roles ranging from hypoxia
signaling, DNA repair, chromatin modifications and oncogenesis
Following the data published by our group attesting that HIF is dispensable for HSC
survival and maintenance, we focused our investigation on HIF-independent
pathways. This manuscript describes the study of the role of an oxygen-sensor
enzyme, member of the 2OG oxygenases and HIF negative regulator, jumonji
domain-containing protein 6 (Jmjd6), in normal and malignant haematopoiesis.
Our knockout studies deleting Jmjd6 specifically within the haematopoietic system
(Jmjd6fl/fl;Vav-iCre) demonstrate that the homeostasis of HSPC pool was
compromised and lymphopoiesis was attenuated in Jmjd6-deficient cohorts. Upon
transplantation, HSCs lacking Jmjd6 exhibited a defective chimerism and impaired
capacity to fully reconstitute haematopoiesis of recipient mice. Thus, Jmjd6 is
essential for HSC self-renewal and maintenance.
Our assessment of the impact of Jmjd6 deletion in the context of inflammatory
response and recovery from treatment with a myelotoxic agent treatment revealed
that Jmjd6 is a positive regulator of HSC homeostasis and recovery from cytotoxic
stress. There are accumulating data on the importance of epigenetics in the development of
haematological malignancies. Being an epigenetic regulator, clearly involved in
RNA splicing, we investigated Jmjd6 as possible player in leukaemogenesis. The
results from our leukaemic studies unravelled a new biological function for Jmjd6 as
a tumour suppressor in Meis1/Hoxa9 murine model.
Altogether, our findings offer important novel insights into the biological functions
of Jmjd6 and pave the way for further studies to discover on the mechanism of action
of this complex enzyme. Our observations add value to the idea that Jmjd6 might
constitute a good candidate for cancer diagnosis, that can be use to ameliorate
patient’s prognosis and that it can be used to help patient prognosis in the future.