Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Target Concepts:
Gene/Protein
Disease
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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
