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 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.
journal_name
Bloodjournal_title
Bloodauthors
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 Hdoi
10.1182/blood-2016-06-724658subject
Has Abstractpub_date
2017-04-13 00:00:00pages
2148-2160issue
15eissn
0006-4971issn
1528-0020pii
blood-2016-06-724658journal_volume
129pub_type
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