RRC ID |
47689
|
著者 |
Nakata Y, Ueda T, Nagamachi A, Yamasaki N, Ikeda KI, Sera Y, Takubo K, Kanai A, Oda H, Sanada M, Ogawa S, Tsuji K, Ebihara Y, Wolff L, Honda ZI, Suda T, Inaba T, Honda H.
|
タイトル |
Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia.
|
ジャーナル |
Blood
|
Abstract |
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 CblQ367P
, a CMML-associated Cbl mutant. CblQ367P
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 CblQ367P
hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. Gem, a gene encoding a GTPase that is upregulated by CblQ367P
, enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1, a gene encoding a transcription factor, was found to cooperate with CblQ367P
and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of CblQ367P
-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.
|
巻・号 |
129(15)
|
ページ |
2148-2160
|
公開日 |
2017-4-13
|
DOI |
10.1182/blood-2016-06-724658
|
PII |
S0006-4971(20)33492-3
|
PMID |
28209720
|
PMC |
PMC5391621
|
MeSH |
Amino Acid Substitution
Animals
Cell Cycle*
Gene Expression Regulation, Enzymologic
Hematopoietic Stem Cells* / metabolism
Hematopoietic Stem Cells* / pathology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Mice
Mice, Transgenic
Monocytes / metabolism
Monocytes / pathology
Monomeric GTP-Binding Proteins / biosynthesis
Monomeric GTP-Binding Proteins / genetics
Mutation, Missense*
Myelopoiesis*
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-cbl* / biosynthesis
Proto-Oncogene Proteins c-cbl* / genetics
Signal Transduction
Up-Regulation*
|
IF |
17.794
|
引用数 |
5
|
WOS 分野
|
HEMATOLOGY
|
リソース情報 |
実験動物マウス |
RBRC01834 |