Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
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Query: UMLS:C0026986 (
myelodysplastic syndrome
)
14,926
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Genetic lesions affecting epigenetic regulators are frequent in
myelodysplastic syndromes
(
MDS
). Polycomb proteins are key epigenetic regulators of differentiation and stemness that act as two multimeric complexes termed polycomb repressive complexes 1 and 2, PRC1 and PRC2, respectively. While components and regulators of PRC2 such as ASXL1 and EZH2 are frequently mutated in
MDS
and AML, little is known about the role of PRC1. To analyze the role of PRC1, we have taken a functional approach testing PRC1 components in loss- and gain-of-function experiments that we found overexpressed in advanced
MDS
patients or dynamically expressed during normal hematopoiesis. This approach allowed us to identify the enzymatically active component
RING1A
as the key PRC1 component in hematopoietic stem cells and
MDS
. Specifically, we found that
RING1A
is expressed in CD34
+
bone marrow progenitor cells and further overexpressed in high-risk
MDS
patients. Knockdown of
RING1A
in an
MDS
-derived AML cell line facilitated spontaneous and retinoic acid-induced differentiation. Similarly, inactivation of
RING1A
in primary CD34
+
cells augmented erythroid differentiation. Treatment with a small compound RING1 inhibitor reduced the colony forming capacity of CD34
+
cells from
MDS
patients and healthy controls. In
MDS
patients higher
RING1A
expression associated with an increased number of dysplastic lineages and blasts. Our data suggests that
RING1A
is deregulated in
MDS
and plays a role in the erythroid development defect.
...
PMID:Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes. 2938 37
