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RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia.

ABSTRACT: To study the oncogenic role of the NRAS oncogene (NRAS(G12V)) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRE-NRAS(G12V) transgene system in Mll-AF9 knock-in mice developing AML. Conditional repression of NRAS(G12V) expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After marked decrease of AML blast cells, myeloproliferative disease (MPD)-like AML relapsed characterized by cells that did not express NRAS(G12V). In comparison with primary AML, the MPD-like AML showed significantly reduced aggressiveness, reduced myelosuppression, and a more differentiated phenotype. We conclude that, in AML induced by an Mll-AF9 transgene, NRAS(G12V) expression contributes to acute leukemia maintenance by suppressing apoptosis and reducing differentiation of leukemia cells. Moreover, NRAS(G12V) oncogene has a cell nonautonomous role in suppressing erythropoiesis that results in the MPD-like AML show significantly reduced ability to induce anemia. Our results imply that targeting NRAS or RAS oncogene-activated pathways is a good therapeutic strategy for AML and attenuating aggressiveness of relapsed AML.

SUBMITTER: Kim WI

PROVIDER: S-EPMC2635074 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia.

Kim Won-Il WI Matise Ilze I Diers Miechaleen D MD Largaespada David A DA

Blood 20081024 5

To study the oncogenic role of the NRAS oncogene (NRAS(G12V)) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRE-NRAS(G12V) transgene system in Mll-AF9 knock-in mice developing AML. Conditional repression of NRAS(G12V) expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After mark ...[more]

PMID: 18952898

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Project description:Implantable chemoport is a very useful device for long-term venous access for infusion of chemotherapeutic drugs and other agents. There are few studies from resource poor countries reporting complications of chemoport. The aim of the present study is to evaluate the feasibility of chemoport insertion without image guidance and by closed technique without direct visualisation of a major vein (mainly IJV) and to study the complications associated with the procedure. This was a prospective observational study which analysed 263 patients who underwent chemoport insertion. The medical records of these patients were analysed for the patient characteristics, diagnosis, port-related complications, and their management. A total of 263 patients who were harbouring either locoregionally advanced or metastatic tumour requiring either chemotherapy or targeted treatment or both were included in the study. In total, 133 (50.57%) were female patients and 130 were male patients (49.43%). A total of 236 patients (89.73%) underwent port insertion procedures under local anaesthesia. None of the patients had any major intra-operative complications. Postoperatively, 4 patients (1.52%) were found to have port catheter malposition; 3 out of this 4 were corrected under IITV guidance as a second procedure under local anaesthesia only. One patient (0.38%) required formal removal and replacement of port. Four patients (1.52%) developed IJV thrombosis requiring port removal and anti-coagulation. One patient (0.38%) developed thrombus in the right atrium. There were 2 port site infections (0.74%) requiring port removal (SSI cat. 5). Low complication rates of port insertion were observed in the present, large, prospective study. Complication rates may be further reduced by using a well-designed procedure, experienced surgeons, an aseptic environment, ultrasound-guided puncture, and fluoroscopy with contrast media.Supplementary informationThe online version contains supplementary material available at 10.1007/s13193-020-01265-6.

Dataset Information

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia.

Publications

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia.

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