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Master Thesis

Effets fonctionnels des mutations de KDM6A dans la leucémie à tricholeucocytes

Abstract : Hairy cell leukemia (HCL) and its variant form (HCL-v) are B-cell lymphoproliferative disorders characterized by BRAF and MAP2K1 mutations responsible of abnormal activation of MAPkinases signaling pathway. Additional mutations to these driver anomalies have been identified. We are interested in the KDM6A gene which codes for a lysine demethylase exerting a role of tumor suppressor. Its loss of expression would sensitize tumor cells to inhibitors of EZH2, a methyltransferase. In order to study the functional impact of the inactivation of KDM6A in HCL, we transfected a CRISPR- Cas9 system targeting exon 4 of the gene in the JVM-3 cell line. The loss of expression of KDM6A in this line promotes activation of the MAPK pathway without modifying the proliferative capacities of the cells, nor their sensitivity to BRAF inhibitors. The edited cells show better resistance to nutrient deprivation, consistent with an increase in the expression of survivin. No increased sensitivity of the modified cells to epigenetic therapies including EZH2 inhibitors has been observed. The inactivation of KDM6A thus appears to contribute to the activation of the oncogenic pathway of MAPK in HCL but does little to modify the capacities of the hairy-cells and their response to chemotherapies and targeted therapies.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-03077527
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Submitted on : Wednesday, December 16, 2020 - 3:34:41 PM
Last modification on : Tuesday, October 19, 2021 - 11:34:51 PM
Long-term archiving on: : Wednesday, March 17, 2021 - 7:34:49 PM

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  • HAL Id : dumas-03077527, version 1

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Margaux Wiber. Effets fonctionnels des mutations de KDM6A dans la leucémie à tricholeucocytes. Sciences pharmaceutiques. 2020. ⟨dumas-03077527⟩

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