Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UMLS:C0019214 (
hepatosplenomegaly
)
4,408
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We investigated the role of
PRMT5
in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key
PRMT5
targets contributing to MPN maintenance.
PRMT5
is overexpressed in primary MPN cells, and
PRMT5
inhibition potently reduced MPN cell proliferation
ex vivo
.
PRMT5
inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2
V617F+
polycythemia vera and leukocyte and platelet counts,
hepatosplenomegaly
, and fibrosis in the MPL
W515L
model of myelofibrosis. Dual targeting of JAK and
PRMT5
was superior to JAK or
PRMT5
inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis
in vivo.
PRMT5
inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link
PRMT5
to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of
PRMT5
inhibitors in MPN. SIGNIFICANCE: Expression of
PRMT5
and E2F targets is increased in JAK2
V617F+
MPN. Pharmacologic inhibition of
PRMT5
alters the methylation status of E2F1 and shows efficacy in JAK2
V617F
/MPL
W515L
MPN models and primary samples.
PRMT5
represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.
This article is highlighted in the In This Issue feature, p. 1611
.
...
PMID:PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2
V617F
-Mutant MPN. 3266 86
