We have previously identified epigenetic dysregulation of HOXA4 in both myeloid and lymphoid leukaemias,23,26 and reported that hypermethylation of HOXA4 is associated with poor response to imatinib in chronic myeloid leukaemia.23,24 Here, we have built on these observations to reveal enrichment for HOXA4 hypermethylation during the course of CLL patient treatment and disease progression, and to provide the first evidence that loss of HOXA4 expression reduces the sensitivity of malignant B cells to multiple chemotherapeutic agents. Here, HOXA4 is linked to lymphoid leukemia.