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

Abstract

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly appreciated as being important for normal hematopoiesis and for hematological malignancies as oncogenes or tumor suppressors, essential RBPs for leukemia maintenance and survival remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis, promotes differentiation, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with 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 due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

“…effector. In line with a recent report demonstrating IGF2BP-family proteins as being critical for YBX1-binding to its target mRNAs [5], IGF2BP2-knockout was shown to mediate resistance to YBX1inactivation (Fig. 6F).…”

“…4E). The ability of YBX1 to impact gene expression by binding and stabilizing mRNAs has been previously demonstrated [2,5]. Therefore, we aimed to assess if the transcripts that are regulated by YBX1 on the RNA level may be targets of YBX1-mRNA binding.…”

“…Cold-shock proteins (CSPs) are a family of multifunctional DNA/ RNA binding proteins that contain a highly conserved nucleic acid binding domain called the cold shock domain. YBX1 is a pleiotropic DNA and RNA binding protein that modulates translation, RNA-stability, mRNA splicing, transcription or cell signaling depending on cell type and genetic background [1][2][3][4][5][6][7][8][9][10]. In humans, eight members of the CSP-family are described: YBX1, YBX2, YBX3, CARHSP1, CSDC2, CSDE1, LIN28A and LIN28B [6].…”

RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis

“…How does RNA m 6 A specifically and precisely regulate the physiological and pathological processes of hematopoiesis. RBPs such as YBX1 regulate the interaction between m 6 A-tagged RNA substrates and m 6 A modifiers (Feng et al, 2021), suggesting that RBPs or cofactors for m 6 A modifiers may act key roles in determining the precision and specificity of RNA m 6 A. In addition, it is necessary to investigate the dynamics of RNA m 6 A profiling during normal and malignant hematopoiesis.…”

“…But the regulatory machinery of IGF2BPs remains elusive. Our recent work revealed that YBX1 cooperates with IGF2BPs to promote the stability of m 6 A-tagged transcripts (Feng et al, 2021), suggesting YBX1 is one component of IGF2BP regulatory machinery. However, what the other factors are involved in the machinery still needs investigation in the future.…”