This study identifies HDAC6 as an overexpressed deacetylase in paediatric and adult B-cell acute lymphoblastic leukaemia (B-ALL) and shows that elevated HDAC6 levels are significantly associated with relapse. Pharmacologic inhibition or shRNA-mediated depletion of HDAC6 reduced CXCL12-driven actin remodelling, transendothelial migration, bone marrow spheroid colonisation and leukaemic dissemination in vivo. HDAC6-dependent motility required the actin-binding protein cortactin, since HDAC6 inhibition did not further reduce migration in cortactin-deficient cells.
Relapse remains the leading cause of treatment failure in B-ALL, with most recurrences arising in the bone marrow and often accompanied by extramedullary involvement. Dissemination requires chemokine-guided egress from bone marrow niches and transendothelial migration, processes that depend on dynamic remodelling of the actin cytoskeleton. Cortactin, an actin-binding protein previously shown to be overexpressed in B-ALL, promotes migration and bone marrow colonisation. Cortactin activity is regulated by post-translational acetylation; deacetylation by HDAC6 increases cortactin affinity for F-actin and supports motility. HDAC6 has been implicated in invasiveness and migration in several malignancies, but its role in B-ALL dissemination and relapse was unclear prior to this work.
The investigators analysed HDAC6 expression in primary samples from two cohorts: 72 paediatric B-ALL patients and 54 adults with newly diagnosed B-ALL. Paediatric samples included paired debut–relapse samples for a subset (n = 16), with each time point treated as an independent biological sample unless otherwise specified. Samples were collected from peripheral blood and bone marrow aspirates before therapy or at relapse, under institutional and national ethical approvals and with written informed consent. CD19+ B cells from healthy donors were used as non-malignant comparators.
B-ALL cell line models (REH and RS4:11) were used to validate HDAC6 expression and to perform mechanistic experiments. The functional role of HDAC6 was interrogated using both pharmacological inhibitors and shRNA-mediated knockdown. Cortactin-depleted cells were employed to test whether HDAC6 effects on motility were cortactin-dependent.
The study evaluated CXCL12-induced actin remodelling as a proximate readout of chemokine-driven motility. Transendothelial migration assays measured the ability of B-ALL cells to traverse endothelial barriers, and bone marrow spheroid colonisation assays assessed capacity to engage and occupy marrow-like niches. In vivo models of leukaemic dissemination were used to determine the impact of HDAC6 manipulation on organ invasion. Across these functional assays, pharmacologic inhibition or genetic depletion of HDAC6 impaired actin polymerisation responses to CXCL12, reduced transendothelial migration, diminished colonisation of bone marrow spheroids and limited dissemination in vivo.
To probe mechanism, cortactin-depleted B-ALL cells were tested alongside controls. HDAC6 inhibition failed to produce an additional reduction in migration in cortactin-deficient cells, indicating that HDAC6 promotes leukaemic motility primarily via a cortactin-dependent pathway. This supports a model in which HDAC6-mediated deacetylation of cortactin enhances cortactin interaction with F-actin and thereby facilitates the cytoskeletal remodelling required for transendothelial migration and tissue invasion.
HDAC6 expression was elevated in patient blasts relative to non-malignant B cells and was significantly associated with relapse in both the paediatric (n = 72) and adult (n = 54) cohorts analysed. For the subset of paired paediatric debut–relapse samples (n = 16), samples were analysed as independent biological samples unless otherwise specified. The association supports the clinical relevance of HDAC6 as a biomarker of dissemination-prone, relapse-associated disease in B-ALL.
The data indicate that HDAC6 is both a biomarker linked to relapse and a functional regulator of cortactin-dependent leukaemic dissemination. Targeting HDAC6—by pharmacologic inhibitors or genetic approaches—reduced actin remodelling, migration, bone marrow colonisation and in vivo organ invasion in experimental models. These findings position HDAC6 as a promising therapeutic target to limit tissue invasion and potentially reduce relapse in B-ALL, pending further preclinical and clinical evaluation.
The source article provides experimental results and cohort associations but this summary does not include effect sizes, specific inhibitor names or dosing regimens, detailed statistical values, or full methodological parameters beyond those reported in the Methods overview. Any specific numeric outcomes, safety data, or clinical trial recommendations not explicitly reported in the source are not included here.