Apport du séquençage haut débit de gènes ciblés dans la leucémie à tricholeucocytes : mise en évidence d'un nouveau gène altéré, KDM6A, dans la forme variante de la maladie

Abstract : Introduction: BRAFV600E detected in more than 80% of Hairy cell leukemia cases. Recently new additional mutation to BRAFV600E have been described. Methods: We selected a panel of 21 relevant genes (defined as Trichopanel) based on literature review of whole exome sequencing studies. At diagnosis, we analyzed 20 HCL and 4 variant form (HCL-v) samples and at relapse 2 HCL and 3 HCL-v.The ratio of variant allele frequency (rVAF) was pondered according to the % of tumor cells estimated by Flow Cytometry. Results and discussion: The Trichopanel was informative for 96% (23/24) of patients and revealed single nucleotide variants (SNVs) in BRAF (n=18), KLF2 (n=4), MAP2K1 (n=3), KDM6A (n=2), CDKN1B (n=2), ARID1A (n=2), CREBBP (n=2) NOTCH1 (n=1) and ARID1B (n=1). BRAFV600E was found in 90% (18/20) of HCL patients and no case in HCL-v patients. In HCL BRAFV600E patients, other mutations were found in 33% (6/18) of cases with a rVAF close to BRAFV600E rVAF. Those data indicating that they are early-onset mutations. All 4 HCL-v patients had SNVs in epigenetic regulation genes e.g.: KDM6A (n=2), CREBBP (n=1) or ARID1A (n=1). KDM6A mutations leads to the loss of the highly-conserved C-terminal region (included Jumomji and Zinc binding domains) which is essential for its demethylase activity. Loss of KDM6A activity may sensibilise tumor cells to demethylating agents such as 5-azacytidine or EZH2 inhibitors. We analyzed at diagnosis and relapse serial samples from 5 patients (2 HCL and 3 HCL-v) and highlighted a clonal evolution of the disease. Conclusion: The Trichopanel is a useful tool for the diagnosis, relapse and prognosis of HCL and HCL-v.
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Master Thesis
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Elsa Maitre. Apport du séquençage haut débit de gènes ciblés dans la leucémie à tricholeucocytes : mise en évidence d'un nouveau gène altéré, KDM6A, dans la forme variante de la maladie. Sciences pharmaceutiques. 2018. ⟨dumas-01953584⟩

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