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• W2977626454 abstract "Abstract Abstract 1207 Targeted pharmacologic therapy with tyrosine kinase inhibitors (TKIs) has become the first-line treatment for patients with CML. However, BCR-ABL+ stem cells resist elimination by continuous TKI treatment in most patients. By contrast, graft-versus-leukemia effects during allogeneic hematopoietic stem cell transplantation can eradicate the disease, suggesting an important role of the immune system in this disease. Besides cytotoxic T cells, natural killer (NK) cells may be involved in immune control of CML. Here, we explored numbers and functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. In 18 patients with newly diagnosed chronic-phase CML, the relative proportions of peripheral blood CD56+CD3- NK cells within the lymphocyte gate were significantly reduced compared to age-matched healthy controls (7.0 ± 5.8% versus 13.1 ± 5.1, p=0.005) and did not recover to normal levels during imatinib-induced remission (9.2 ± 5.9%, p=0.024, follow-up 10–59 months). Functional experiments showed reduced in vitro expansion of CML NK cells at diagnosis in response to stimulation with 4-1BBL/mbIL-15 transduced K562 cells (23.5 ± 14.46 fold vs 41.2 ± 7.2 fold, p=0.013) and under imatinib treatment (31.5 ± 10.5 fold, p=0.03), and a reduced degranulation response to K562 target cells by CD107 upregulation (2.8 ± 2.7% at diagnosis and 9.0 ± 13.2% under treatment, vs. 19.1 ± 8.0% in controls, p=0.003 and p=0.045, respectively). To investigate, whether the defective NK-cell compartment in CML is a consequence of the characteristic BCR-ABL-induced myeloproliferation, we addressed the quantity and functionality of NK cells in a double transgenic mouse model of human CML. Consistent with the results in human CML, the relative proportions of NK1.1+ NK cells among total splenic lymphocytes were significantly reduced in BCR-ABL induced mice (6.4 ± 3.5% vs. 14.7 ± 1.8%, p=0.005). Moreover, compared to NK cells isolated and expanded from BCR-ABL-non-induced control mice, the degranulation response of splenic NK cells from BCR-ABL+ mice to YAC-1/NIH-3T3 cells was significantly decreased (25.7 ± 1.6% vs 42.4 ± 5.6%, p=0.002), and analogous results were obtained with NK cells expanded from bone marrow of these mice (7.7 ± 4.9% vs. 25.0 ± 7.1%, p=0.033). These results suggest both quantitative and qualitative defects within the NK cell compartment in CML. Further work will aim at identifying the underlying mechanisms of the NK cell deficiency in CML, and the development of strategies to utilize NK cells for immunotherapy of CML. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees." @default.
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• W2977626454 date "2010-11-19" @default.
• W2977626454 modified "2023-10-17" @default.
• W2977626454 title "Disturbed NK Cell Compartment In Human CML and Bcr-Abl Positive Mice." @default.
• W2977626454 doi "https://doi.org/10.1182/blood.v116.21.1207.1207" @default.
• W2977626454 hasPublicationYear "2010" @default.
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