Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0019829 (
Hodgkin's disease
)
30,247
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-
Hodgkin
lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)
+
or ALK
-
, based on the presence or absence of
ALK
rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene,
MSC
E116K
, exclusively in ALK
-
ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of
MSC
E116K
for ALK
-
ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting
DUSP22
rearrangements.
Musculin
is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSC
E116K
acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of
MYC
and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene
E2F2
as a direct transcriptional target of musculin. MSC
E116K
reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the
MSC
promoter. Finally, ALCL cells expressing
MSC
E116K
were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent
MSC
mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.
...
PMID:Recurrent
MSC
E116K
mutations in ALK-negative anaplastic large cell lymphoma. 3110 22
