Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenic NRAS mutations are prevalent in human myeloid leukemia, especially in chronic myelomonocytic leukemia (CMML). NrasG12D mutation at its endogenous locus in murine hematopoietic stem cells (HSCs) leads to CMML and acute T-cell lymphoblastic lymphoma/leukemia in a dose-dependent manner. Hyper-activated MAPK and STAT5 pathways by oncogenic Nras contribute to the leukemogenesis in vivo. However, it is unclear whether these conclusions remain true in a more human relevant model. Here, we evaluated the effects of NRASG12D on human hematopoiesis and leukemogenesis in vitro and in vivo by ectopically expressing NRASG12D in human cord blood stem/progenitor cells (hSPCs). NRASG12D expressing hSPCs preferentially differentiated into myelomonocytic lineage cells, demonstrated by forming more colony forming unit-macrophages than control hSPCs in cultures. Transplantation of NRASG12D expressing hSPCs initiated myeloproliferative neoplasm in immune deficiency mice. All the recipient mice died of myeloid tumor burdens in spleens and bone marrows and none developed lymphoid leukemia. Phospho-flow analysis of CD34(+) CD38(-) hSPCs confirmed that NRASG12D hyper-activated MAPK, AKT and STAT5 pathways. Our study provides the strong evidence that NRASG12D mutation mainly targets monocytic lineage cells and leads to myelomonocytic proliferation in vivo in a highly human relevant context.
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PMID:Oncogenic NRAS hyper-activates multiple pathways in human cord blood stem/progenitor cells and promotes myelomonocytic proliferation in vivo. 2669 39

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.
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PMID:Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia. 2840 21