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Published on: October 11, 2018
HDAC6 is a biomarker of leukaemic dissemination and relapse in B-ALL
Karina E Jiménez-Camacho1,2,3, Hilda Vargas-Robles1, Joseph Adomako1
1Department of Molecular Biomedicine, CINVESTAV, Mexico-City, Mexico.
Background/Objectives:
Relapse remains the leading cause of treatment failure in B-cell acute lymphoblastic leukaemia (B-ALL), highlighting the need for biomarkers and therapeutic targets that limit leukaemic dissemination. We investigated whether histone deacetylase 6 (HDAC6), a regulator of cortactin-dependent actin remodelling, contributes to B-ALL progression and relapse.
Subjects/Methods:
HDAC6 expression was analysed in cohorts of 72 paediatric and 54 adult patients with B-ALL and validated in B-ALL cell lines. The functional role of HDAC6 was assessed using pharmacological inhibition and shRNA-mediated knockdown in assays of CXCL12-induced actin remodelling, transendothelial migration, bone marrow colonisation and leukaemic dissemination in vivo. Cortactin-depleted cells were used to determine pathway dependence.
Results:
HDAC6 expression was elevated in B-ALL cell lines and patient samples and was significantly associated with relapse in both patient cohorts. Pharmacological inhibition or genetic depletion of HDAC6 impaired CXCL12-induced actin remodelling, transendothelial migration, bone marrow colonisation and leukaemic dissemination. HDAC6 inhibition failed to further reduce migration in cortactin-deficient cells, indicating that HDAC6 promotes leukaemic motility through cortactin.
Conclusions:
HDAC6 is a clinically relevant biomarker associated with B-ALL relapse and a critical regulator of cortactin-dependent leukaemic dissemination. Targeting HDAC6 represents a promising therapeutic strategy to limit tissue invasion and reduce relapse.
