HDAC7 induction prevents immune escape in high-risk infant pro-B-ALL

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Infant pro-B acute lymphoblastic leukemia (pro-B-ALL) with t(4;11) rearrangement presents an aggressive phenotype and very poor response to conventional chemotherapy. Moreover, immune escape mechanisms such as lineage switch involve the loss of B cell markers, leading to CD19-CAR-T therapy failure. Our previous findings have demonstrated that histone deacetylase HDAC7, a key factor in B cell differentiation, is underexpressed in t (4;11) pro-B-ALL. However, the precise induction of HDAC7, mediated by a previously defined drug combination, blocks t (4;11) pro-B-ALL cells from acquiring myeloid cell features and induces acquisition of lymphoid genes such as CD19, both in vitro and in vivo. In parallel, ex vivo culture of t (4;11) pro-B-ALL primary cells has revealed the presence of a subpopulation with low CD19 expression. Remarkably, the use of HDAC7-inducing therapy shifts this CD19 low cells into CD19 high population, thus reducing the ration of CD19 low cells, most likely to undergo lineage switch and display immunotherapy resistance. Therefore, HDAC7 induction is a promising therapeutic strategy to improve response of t (4;11) pro-B-ALL patients to CD19 CAR-T cell therapy. Publication History Article published online: 10 May 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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