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:C0038002 (
splenomegaly
)
9,873
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the
Cbl
gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant
Cbl
in CMML pathogenesis, we generated conditional knockin mice for
Cbl
that express wild-type
Cbl
in a steady state and inducibly express
Cbl
Q367P
, a CMML-associated
Cbl
mutant.
Cbl
Q367P
mice exhibited sustained proliferation of myelomonocytes, multilineage dysplasia, and
splenomegaly
, which are the hallmarks of CMML. The phosphatidylinositol 3-kinase (PI3K)-AKT and JAK-STAT pathways were constitutively activated in
Cbl
Q367P
hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity.
Gem
, a gene encoding a GTPase that is upregulated by
Cbl
Q367P
, enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition,
Evi1
, a gene encoding a transcription factor, was found to cooperate with
Cbl
Q367P
and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of
Cbl
Q367P
-bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant
Cbl
-induced CMML and propose a possible molecular targeting therapy for mutant
Cbl
-carrying CMML patients.
...
PMID:Acquired expression of
Cbl
Q367P
in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia. 2840 21
