YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner

• DOI: 10.1182/blood.2020009676
• Publication Date: 2021-03-25T00:55:53Z
• Authors: Mengdie Feng; Xueqin Xie; Guoqiang Han; Tiantian Zhang; Yashu Li; Yicun Li; Rong Yin; Qifan Wang; Tong Zhang; Peipei Wang; Jin Hu; Ying Cheng; Zhuying Gao; Jing Wang; Jiwei Chang; Manman Cui; Kexin Gao; Jihua Chai; Weidong Liu; Chengli Guo; Shaoguang Li; Lingbo Liu; Fuling Zhou; Jianjun Chen; Haojian Zhang
• Keywords: 0301 basic medicine; mice; Adenosine; Cell Survival; bcl2 gene; Apoptosis; cell survival; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Hemic and Lymphatic Diseases; Neoplasms; Animals; Humans; rna; RNA, Neoplasm; Cancer Biology; Myeloid Neoplasia; Gene Expression Regulation, Leukemic; Protein Stability; rna-binding proteins; leukemia; apoptosis; RNA-Binding Proteins; Hematology; Hematopoiesis; 3. Good health; messenger; Mice, Inbred C57BL; Leukemia, Myeloid, Acute; Oncology; Proto-Oncogene Proteins c-bcl-2; Y-Box-Binding Protein 1; myeloid; bcl-2 protein; Gene Deletion

Abstract RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.