A small molecular compound CC1007 induces cross-lineage differentiation by inhibiting HDAC7 expression and HDAC7/MEF2C interaction in BCR-ABL1\u2212 pre-B-ALL

Zhihua Wang,Yongheng Chen,Yang Zhang,Guoyu Hu,Yunxiao Xu,Zhao Cheng,Lin Chen,Sufang Liu,Guangsen Zhang,Shicong Zhu,Mingyang Deng,Hongling Peng,Yunya Luo,Ruijuan Li

doi:10.1038/s41419-020-02949-1

Abstract

Histone deacetylase 7 (HDAC7), a member of class IIa HDACs, has been described to be an important regulator for B cell development and has a potential role in B cell acute lymphoblastic leukemia (B-ALL). CC1007, a BML-210 analog, is designed to indirectly inhibit class IIa HDACs by binding to myocyte enhancer factor-2 (MEF2) and blocking the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of these targets. In this study, we investigated the anticancer effects of CC1007 in breakpoint cluster region-Abelson 1 fusion gene-negative (BCR-ABL1−) pre-B-ALL cell lines and primary patient-derived BCR-ABL1− pre-B-ALL cells. CC1007 had obvious antileukemic activity toward pre-B-ALL cells in vitro and in vivo; it also significantly prolonged median survival time of pre-B-ALL-bearing mice. Interestingly, low dose of CC1007 could inhibit proliferation of BCR-ABL1− pre-B-ALL cells in a time-dependent manner not accompanied by significant cell apoptosis, but along with cross-lineage differentiation toward monocytic lineage. From a mechanistic angle, we showed that HDAC7 was overexpressed in BCR-ABL1− pre-B-ALL cells compared to normal bone marrow samples, and CC1007 could reduce the binding of HDAC7 at the promoters of monocyte–macrophage-specific genes via inhibition of HDAC7 expression and HDAC7:MEF2C interaction. These data indicated that CC1007 may be a promising agent for the treatment of BCR-ABL1− pre-B-ALL.

Highlights

B lymphopoiesis is a complicated process that takes place in a step-by-step manner and involves several cellular transitions, including cell commitment and differentiation
When BCR-ABL1− pre-B cell acute lymphoblastic leukemia (B-ALL) cells were exposed to low dose of CC1007 (1.25 μM) for 7 days and co-immunoprecipitation was done in parallel on the third, fifth, and seventh day, the binding of Histone deacetylase 7 (HDAC7) and MEF2C became gradually weak and followed incubation-time prolongation (Fig. 6e), which was consistent with the immunofluorescence localization results where the color yellow indicated that the HDAC7:MEF2C complex was observed in the nuclei in the absence of CC1007 (Fig. 6f)
In this study, we demonstrated that CC1007 had obvious antileukemic activity toward pre-B-ALL cells in vitro and induces BCR-ABL1− pre-B-ALL cells crosslineage differentiation toward monocytic lineage (Fig. 8); it displays a strong antileukemic effect on primary pre-B-ALL xenografts and significantly prolonged median survival time of pre-B-ALL-bearing mice

Summary

Introduction

B lymphopoiesis is a complicated process that takes place in a step-by-step manner and involves several cellular transitions, including cell commitment and differentiation. Cxcl[10], which are involved in the regulation of phagocytosis and immune modulation of monocytes, displayed inductive overexpression in a dose- and time-dependent manner after low dose of CC1007 treatment (Fig. 4d), suggesting that CC1007 could induce cross-lineage differentiation in BCR-ABL1− pre-B-ALL cells.

Results

Conclusion