HDAC7 induction combined with standard-of-care chemotherapy provides a therapeutic advantage in t(4;11) infant B-ALL

Infants diagnosed with acute lymphoblastic leukemia (B-ALL) and t(4;11) chromosomal rearrangements represent a subset of patients with poor therapeutic response. t(4;11) B-ALL cells exhibit low levels of HDAC7, which is essential for optimal B lymphocyte differentiation. Here, we show that HDAC7 silencing in this malignancy is mediated by epigenetic mechanisms involving the chromatin remodeler EZH2 and the KMT2A-AFF1 fusion protein. Remarkably, the menin inhibitor MI-538 restores HDAC7 expression, and this effect is enhanced by the addition of the class I HDAC inhibitor chidamide. This treatment drives leukemic pro-B cells towards a more differentiated and less malignant state, thereby impairing aberrant proliferation. In addition to reducing the malignant capacity of leukemic cells in vitro, addition of MI-538 and chidamide to standard chemotherapy shows promise in reducing the engraftment of t(4;11) pro-B-ALL cells in vivo and delaying relapse. Finally, the newly developed therapy increases the ex vivo glucocorticoid sensitivity of t(4;11) pro-B-ALL primary cells. Overall design: SEM-K2 cells (derived from an infant diagnosed of MLL-AF4+ iB-ALL) were treated with MI-538 and Chidamide. These compounds are epigenetic drugs that impair the activity of KMT2A-AFF1 by blocking specific cofactors coactivators (Menin and class I HDACs). We have previously observed that the treatment with these compounds induces HDAC7 expression, which is a biomarker associated to an improved prognosis. In this RNAseq experiment we aim to compare the transcriptional profile of SEM-K2 cells treated with this combinatorial therapy with counterparts cells treated with DMSO (as vehicle).